亚砷酸钠诱引角质形成细胞恶性转化及其机制研究
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摘要
在流行病学的研究报告中充分显示无机砷为人类致癌物,长期无机砷暴露除引发皮肤癌外也会有肺癌、膀胱癌、肝癌等癌症的发生。然而动物实验尚未直接证实砷化物的致癌性。为进一步了解无机砷的致癌性,并从人类皮肤角质形成细胞起源角度探索砷致皮肤癌发生的分子机制将为进一步理解砷致皮肤癌发生发展的机理提供新的证据,同时也为寻找对早期预防、早期诊断和治疗有价值的新的分子标记提供线索。由于皮肤是无机砷的主要靶组织,也是对砷毒性最敏感的组织之一,因此正常人皮肤角质形成细胞对于砷毒性作用的研究具有重要的实际意义。HaCaT永生化的人角质形成细胞株(以下简称HaCaT细胞)来源于正常人皮肤,与正常皮肤角质形成细胞分化特性相似,可无限传代,但无致瘤性,是体外研究砷致癌等作用机制的理想模型。
因此本研究以HaCaT细胞为研究对象,采用存在于自然界中对人体毒性较大的三价无机砷：亚砷酸钠(sodium arsenite, NaAsO2)进行长期(30代,约4个月)、低浓度诱导其恶性转化。结果发现,NaAsO2处理HaCaT细胞至25代后(约100天),以皮下注射方式将细胞注射进入到裸鼠左腋下,可见肿瘤的形成,肿瘤组织切片观察判定是鳞状细胞癌(squamous cell carcinoma, SCC),属于砷引起皮肤癌的一种类型。长期低水平砷暴露诱导成致瘤性的HaCaT细胞群中可能“存在的”为数不多的具有自我更新能力、分化潜能的癌干细胞(Cancer stem cells, CSCs),而CD44v6是其潜在的特异性分子标志物。肿瘤干细胞标志物CD44v6的活化可能与NaAsO2对NF-κ B的激活和对P53的抑制有关。
采用基因芯片技术、荧光定量PCR技术分析NaAsO2处理导致致瘤性转化的HaCaT细胞和同期配对的对照组HaCaT细胞的基因表达谱变化,通过生物信息学分析发现细胞增殖、免疫系统反应、细胞生长、细胞粘附运动等生物过程的失调或改变在长期低浓度NaAsO2诱导HaCaT细胞致瘤性转化过程中发挥重要作用。差异基因参与多条与肿瘤及癌干细胞密切相关的信号通路,如Wnt、MAPK、NOTCH、p53、cell cycle、apotosis、Jak-STAT、 TGF-beta、NF-κB、PI-3K/AKT等信号通路。与这些生物过程、信号通路密切相关的基因可能是砷致HaCaT细胞恶性转化过程中的关键因子,如鼠类胸腺瘤病毒(v-akt)同源体2/β-rac蛋白激酶(v-akt murine thymoma viral oncogene homolog2/protein kinase Bβ, AKT2),骨髓细胞瘤病毒同源的MYC原癌基因(v-myc myelocytomatosis viral oncogene homolog, MYC), MDM2癌基因(Mdm2p53binding protein homolog, murine double mimute2, MDM2),细胞周期蛋白D3(cyclin D3, CCND3),丝裂原活化蛋白激酶3K14(mitogen-activated protein kinase kinase kinase14, MAP3K14), Jak蛋白酪氨酸激酶-1(Janus kinase1, JAK1),基质金属蛋白酶-9(matrix metallopeptidase9, MMP9), PTEN抑癌基因(Phosphatase and tensin homolog deleted on chromosome ten, PTEN), ATM抑癌基因(Ataxia telangiectasia mutated, ATM),信号传导子及转录激活子5A(Signal transducer and activator of transcription5A, STAT5A), Rho相关蛋白激酶2(Rho-associated, coiled-coil containing protein kinase2, ROCK2)等。
第一章长期低浓度砷剂诱引角质形成细胞恶性转化的研究
为进一步了解无机砷的致癌性,因此利用0.05ppm(约0.4μM)NaAsO2处理人永生化角质形成细胞株(HaCaT)大约4个月,探讨暴露在长时间低浓度无机砷下的HaCaT细胞的生长情形,诱导HaCaT细胞发生致瘤性转化,为进一步探索、分析转化过程中肿瘤干细胞标志物表达变化和基因表达谱的变化提供基础。
HaCaT细胞常规培养于完全培养基DMEM。长时间细胞培养的做法是接种5×105个HaCaT细胞于100ml培养瓶中并且分别处理0,0.05ppm NaAsO2,当满2天时更换新的DMEM培养液,满4天时则进行隔代培养。总共隔代培养30代,约4个月中NaAsO2持续存在于DMEM培养液中。细胞培养期间,倒置显微镜下观察每代细胞形态的变化并拍照。并进行软琼脂克隆形成率(Colony-forming efficiency, CFE)等实验验证细胞的转化、应用MTT法测定转化细胞的增殖能力、流式细胞术(Flow Cytometry, FCM)检测转化细胞的细胞周期、并将恶性转化和同期配对传代的对照组HaCaT细胞注射于Balb/c裸鼠左侧腋窝皮下,观察肿瘤形成情况,并作组织切片、HE染色后进行组织病理学鉴定。
NaAsO2处理HaCaT细胞至25代后(约100天),以皮下注射方式将细胞打入裸鼠左腋下,可见肿瘤的形成。并且借由观察肿瘤组织切片判定是鳞状细胞癌,是砷引起皮肤癌的一种类型。经长期低浓度无机砷刺激的HaCaT细胞发生了致瘤性转化。此外,HaCaT细胞还有下列几项的变化：(1)软琼脂克隆形成实验表明NaAs02长期低浓度处理的细胞具有了非停泊性依赖生长的特性。(2)光镜下观察到细胞于培养瓶内长满时有较高的细胞密度,出现排列紊乱、重叠交叉生长现象,并出现多核巨细胞。(3)MTT检测结果表明长期低浓度NaAs02处理的HaCaT细胞的增殖能力较对照组细胞明显增强。(4)NaAsO2处理的HaCaT细胞较未处理的细胞有更多的细胞处于细胞周期的S、G2/M期,说明受NaAsO2处理细胞的增殖能力旺盛。
本部分实验成功建立了低水平NaAsO2慢性处理所致HaCaT细胞恶性转化模型,从而为进一步探讨砷化物所致细胞恶性转化分子机制提供了基础。
第二章长期低浓度砷剂诱引角质形成细胞恶性转化过程中肿瘤干细胞标志物的表达及意义
本部分旨在探讨肿瘤干细胞在砷致人角质形成细胞恶性转化中的作用及其影响因素,以期发现或揭示砷致皮肤癌过程中的肿瘤干细胞特异性标志物及相关信号转导通路。分别对第0,5,10,15,20,25,30代低浓度NaAsO2处理的HaCaT细胞和同期配对的对照组HaCaT细胞滴片进行荧光免疫组化(Immunofluorescence, IF)染色；同时提取上述不同时间点两组细胞的总蛋白,利用蛋白印迹(Western blotting, WB)等实验技术对可能存在的肿瘤干细胞标志物进行筛选,与其他检测指标进行相关分析。并分析其影响因素。
结果显示,长期低浓度NaAsO2处理的HaCaT细胞中,肿瘤干细胞标志物CD44v6蛋白含量有逐渐增加的表现；对照组CD44v6蛋白含量未发现明显变化。恶性转化的HaCaT细胞(第25代)其CD44v6蛋白含量比同期对照组HaCaT细胞(第25代)显著增加(P<0.05)。NaAsO2处理组HaCaT细胞在15代后,CD44v6阳性表达显著增加,定位于细胞膜,在25代和30代约有8%的阳性率。对CD44v6的表达与软琼脂克隆阳性率之间的关系进行分析,结果发现,r=0.949,P=0.01,两者呈正相关性。肿瘤干细胞标志物CD44v6表达变化可能与砷致NF-κB激活、P53抑制有关。
实验结果提示,长期低水平砷暴露所致皮肤损伤或癌组织中可能“存在的”为数不多的具有自我更新能力、分化潜能的癌干细胞,而CD44v6是其潜在的特异性分子标志物。肿瘤干细胞标志物CD44v6的活化可能与NaAsO2对NF-K B的激活和对P53的抑制有关。
第三章长期低浓度砷剂诱引角质形成细胞恶性转化的基因表达变化
本部分实验目的是探讨NaAsO2诱引人类皮肤细胞HaCaT恶性转化过程中基因表达谱的改变,分析差异基因的生物学意义,进而揭示在NaAsO2诱导HaCaT细胞致瘤性转化过程中可能起关键作用的生物学通路和分子,为理解砷暴露致皮肤癌发生的分子机制提供线索。实验方法：提取正常HaCaT细胞和转化HaCaT细胞的总RNA,应用高通量的基因芯片技术分析转化HaCaT细胞和正常对照HaCaT细胞基因表达谱的改变,运用实时定量PCR技术验证芯片的结果,并结合生物信息学分析对差异基因进行功能分类,同时探讨差异基因之间以及差异基因与其他基因之间可能的网络联系。
结果发现,恶性转化的HaCaT细胞和正常对照HaCaT细胞共发现2,871个表达差异基因(P<0.05时,差异倍数≥2),约占芯片探针总数的6.1%(2,871/44,000)。其中1,415个基因表达上调,1,456个基因表达下调。其中表达上调的基因包括鼠类胸腺瘤病毒(v-akt)同源体2/β-rac蛋白激酶(v-akt murine thymoma viral oncogene homolog2/protein kinase Bβ,AKT2),骨髓细胞瘤病毒同源的MYC原癌基因(v-myc myelocytomatosis viral oncogene homolog, MYC), MDM2癌基因(Mdm2p53binding protein homolog, murine double mimute2, MDM2),细胞周期蛋白D3(cyclin D3, CCND3),丝裂原活化蛋白激酶3K14(mitogen-activated protein kinase kinase kinase14, MAP3K14)等；表达下调的基因有Jak蛋白酪氨酸激酶-1(Janus kinase1, JAK1),基质金属蛋白酶-9(matrix metallopeptidase9, MMP9), PTEN抑癌基因(Phosphatase and tensin homolog deleted on chromosome ten, PTEN),ATM抑癌基因(Ataxia telangiectasia mutated, ATM),信号传导子及转录激活子5A(Signal transducer and activator of transcription5A,STAT5A), Rho相关蛋白激酶2(Rho-associated, coiled-coil containing protein kinase2, ROCK2)等。实时荧光定量PCR分析上述基因在两组细胞中的表达,进一步证实了芯片结果的可靠性。用Gene Ontology(GO)数据库将差异基因进行功能注释,结果发现差异基因产物主要参与细胞增殖(cell proliferation)、免疫系统反应(immune system process).细胞生长(cell development)、细胞粘附(cell adhesion)等与肿瘤发生、发展相关密切的功能调节。KEGG和Biocarta数据库分析差异基因之间的相互作用网络,结果发现差异基因参与多条信号通路,其中已知Wnt、MAPK、NOTCH、p53、cell cycle、apotosis、Jak-STAT、TGF-beta、 NF-κB、PI-3K/AKT等信号通路与肿瘤及癌干细胞密切相关。AKT2, JAK1, MMP9, MYC, PTEN, ATM, MDM2, STAT5A, CCND3, MAP3K14和ROCK2等与多条通路有关,可能在NaAsO2诱导HaCaT细胞的转化过程中发挥关键的作用。
以上结果提示：长期低浓度NaAsO2处理直接引起HaCaT细胞基因表达改变,砷暴露导致的细胞增殖、免疫调节、细胞粘附运动失衡或改变在其诱导HaCaT细胞致瘤性转化过程中可能发挥重要作用,Wnt、MAPK等多条信号通路参与砷诱导HaCaT细胞致瘤性转化过程,AKT2, JAK1, MMP9, MYC, PTEN, ATM, MDM2, STAT5A, CCND3, MAP3K14和ROCK2等基因可能是这一过程中的关键分子。
结论
1.人永生化角质形成细胞株HaCaT在长期低水平NaAsO2作用下发生了致瘤性转化。
2.长期低水平砷暴露诱导成致瘤性的HaCaT细胞群中可能“存在的”为数不多的具有自我更新能力、分化潜能的癌干细胞,而CD44v6是其潜在的特异性分子标志物。
3.肿瘤干细胞标志物CD44v6的活化可能与NaAsO2对NF-κB的激活和对P53的抑制有关。
4.分析了正常HaCaT细胞、转化HaCaT细胞的基因表达变化。在转化过程中发生改变的基因主要参与调节细胞增殖、免疫反应、细胞粘附运动等生物学过程；以及Wnt、MAPK、NOTCH、p53、cell cycle、apotosis、Jak-STAT、 TGF-beta、NF-kB、PI-3K/AKT等多条信号通路；AKT2, JAK1, MMP9, MYC, PTEN, ATM, MDM2, STAT5A, CCND3, MAP3K14和ROCK2等基因可能是转化过程中的关键分子。
Epidemiological studies from many countries and observed that chronic exposure to arsenic caused primarily skin cancer, but also lung cancer, urinary bladder cancer and liver cancer. However, inorganic arsenic fails to induce tumors in most laboratory animals. To explore the mechanisms of arsenic carcinogenesis, and to investigate the molecular mechanism of arsenic-induced skin cancer from cellular origin aspect may provide us some novel clues for explaining further development and progression of arsenic-induced skin cancer and for finding the valuable biomarkers of early diagnosis, prevention and treatment. The skin is a major target of arsenic exposure and one of the most sensitive tissues to chronic arsenic exposure. Thus, human skin keratinocytes are widely used for study of the arsenic toxicity. The human spontaneously immortalized skin keratinocytes (HaCaT) was originally derived from normal human adult skin, which maintains full epidermal differentiation capacity and is immortalized but nontumorigenic. It is an ideal model for the study of arsenic carcinogenicity.
Here, we repeatedly exposed the HaCaT cell line to an environmentally relevant level of arsenic (0.05ppm, about0.4u M) in vitro for about4months, determined the acquired cancer phenotype. Through a continuous exposure of HaCaT to non-toxic doses of sodium arsenite(0.05ppm) for several months,HaCaT cells became apparently tumorigenic in nude mice, pathological studiesof xenogratf tumor sections showed a highly undifferentiated, pleomorphicnature of tumors from arsenic-treated HaCaT cells, and the tumor testified assquamous cell carcinomas (SCC), a type of cancer that induced by arsenic inskin.
The present results suggest that the malignant population from chronic,low-level arsenic-treated HaCaT cells may develop from a rare population,which "the existence" of cancer stem cells (CSCs) with the capacity ofself-renewal and potential differentiation. CD44v6may be a biomarker ofarsenic-induced neoplastic transformation in human skin cells, and that arsenicpromotes malignant transformation in HaCaT cells through its activation ofNF-kB and inactivation of P53stimulated expression of CD44v6.
The changes of gene expression profile between the arsenic-treated cellsand passage-matched control cells was obtained through oligo microarraydetection and qPCR respectively. Bioinformaties analysis suggested that theimbalance between cell proliferation, immune system process, cell developmentand cell adhesion, etc. may play an important role in arsenic-induced neoplastictransformation of HaCaT cells. From the pathway comparison(Base on KEGGand Biocarta database), the differentially expressed genes involved in severalsignaling pathways that play an important role in cancer and cancer stem cells,such as Wnt, MAPK, Jak-STAT, TGF-beta, NOTCH, PI-3K/AKT and NF-kBsignaling pathway. Alteration of gene expression patterns and especiallyup-regulation of AKT2, MYC, DMD2, CCDN3, MAP3K14anddown-regulation of JAK1, PTEN, ATM, STAT5A may account for the malignanteffect of inorganic arsenic.
Part one Study of sodium arsenite-induced neoplastic transformation in human skin HaCaT cells
To explore the mechanisms of arsenic carcinogenesis, we have investigated the growth property and induced malignant transformation in spontaneously immortalized human skin keratinocytes (HaCaT), that were continuously exposed to non-toxic doses of arsenite (0.05ppm, about0.4μM) for approximately4months. This research was intended to provide a foundation for further work in analysis of cancer stem cells specific molecular marker and gene expression profile during arsenic-induced HaCaT cells malignant transformation.
The cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with10%fetal bovine serum (FBS), and antibiotics (100U/ml penicillin and100μg/ml streptomycin). For chronic exposure, cells were maintained continuously in a medium containing0.05ppm of NaAsO2for30passages (about4months). Morphological change was observed under light microscope or transmission electron microscope. We assessed colony forming efficiency (CFE) in soft agar every5passages (3weeks) to ascertain acquired malignant phenotype. Meanwhile, the proliferative ability of arsenic-treated HaCaT cells and passage-matched control cells were detected by MTT analysis, cell cycle was measured by flow cytometry (FCM). Once the soft agar colony assay suggested that arsenic-induced carcinogenic conversion had occurred, arsenic-treated and control cells were injected subcutaneously on the left axillary fossa of male Balb/c nude mice, animals were observed for tumor formation over a6-month period, and tumor tissue was examined by immunohistochemistry.
Through a continuous exposure of HaCaT to non-toxic doses of arsenite(0.05ppm) over25passages, HaCaT cells became apparently tumorigenic in nude mice, and the tumor testified as squamous cell carcinomas (SCC), a type of cancer that induced by arsenic in skin. In addition, we have observed the following changes caused by long term, low-level exposure to arsenite in HaCaT cells:(1) higher colony forming efficiency on soft agar;(2) higher cell density at confluence and exhibited morphological alterations with the frequent occurrence of giant multinuclear cells;(3) Higher capacity of proliferation; and (4) more population in S, G2/M phase.
These results suggested that HaCaT cells treated by chronic, low-level arsenite have neoplastic transformation. The transformed cells provided us basis for further study.
Part two The expression and significance of the cancer stem cell markers in arsenic-induced neoplastic transformation in human skin cells
To explore the effects of long-term, low concentration arsenic on cancer stem cell markers function in HaCaT cells. After treatment of Oppm,0.05ppm sodium arsenite for0passage,5passages,10passages,15passages,20passages,25passages and30passages. Western blotting and immunofluorescence staining were used to observe the expression of CD44v6, CD133, NF-κB and p53protein in arsenic-treated HaCaT cells and passage-matched control cells at different time points.
The research results show that the protein level of cancer stem cell marker, CD44v6was up-regulated after chronic, low level sodium arsenite administration while CD133protein level has no obvious change. CD44v6protein level increased steadily duration of arsenic treatment, and has significance difference from passage-matched control cells at25passages (P＜0.05). After treatment of0.05ppm sodium arsenite for15passages, CD44v6expression in arsenic-treated cells increased sharply, CD44v6immunoreactivity positive cells localized primarily in the membrane of some HaCaT cells, CD44v6positive ratio of CD44v6immunoreactivity positive cells is about8%at25and30passages of arsenic-treated cells. Moreover, the extent of CD44v6immunoreactivity in arsenic-treated cells was found to positively correlate with the cloning efficiency in soft agar (r=0.949, P=0.01). Arsenic exposure promoted abnormal expression of CD44v6possibly involved in its activation of NF-κB and inactivation of P53.
The present results suggested that the malignant population from chronic, low-level arsenic-treated HaCaT cells may develop from a rare population, which "the existence" of cancer stem cells (CSCs) with the capacity of self-renewal and potential differentiation. CD44v6may be a biomarker of arsenic-induced neoplastic transformation in human skin cells, and that arsenic promotes malignant transformation in human skin cells through its activation of NF-κB and the inactivation of P53.
Part three Arsenic promotes malignant transformation in human epidermal keratinocytes through alteration of gene expression patterns
To get more insight into the carcinogenic mechanism of arsenic action, we performed genome-wide expression profiling of arsenic-treated and untreated HaCaT cells using oligo microarrays (Agilent Whole Human Genome Oligo Microarray) that contain41,000genes. Data analysis included hierarchical clustering of differentially expressed genes, gene ontology enrichment analyses and pathway analysis. Eleven genes that involved in cancer were selected for further evaluation by quantitative RT-PCR (qPCR).
Gene expression profile analysis revealed that2,871were differentially expressed between malignant HaCaT cells and normal HaCaT cells. Of these,1,415were significantly up-regulated and1,456were statistically significantly down-regulated in malignant HaCaT cells. Up-regulated genes included AKT2(v-akt murine thymoma viral oncogene homolog2/protein kinase Bβ), MYC(v-myc myelocytomatosis viral oncogene homolog), MDM2(Mdm2p53binding protein homolog, murine double mimute2), CCND3(cyclin D3), MAP3K14(mitogen-activated protein kinase kinase kinase14), etc. Down-regulated genes had Jakl (Janus kinase1), MMP9(matrix metallopeptidase9), PTEN (Phosphatase and tensin homolog deleted on chromosome ten), ATM (Ataxia telangiectasia mutated), STAT5A(Signal transducer and activator of transcription5A), ROCK2(Rho-associated, coiled-coil containing protein kinase2),etc. The differentially expressed genes with functions that include cell proliferation, immune system process, cell development and cell adhesion, and involved in several signaling pathways that play an important role in cancer and cancer stem cells, such as Wnt, MAPK, Jak-STAT, TGF-beta, NOTCH, PI-3K/AKT and NF-κB signaling pathway. Alteration of gene expression patterns and especially up-regulation of AKT2, MYC, DMD2, CCDN3, MAP3K14and down-regulation of JAK1, PTEN, ATM, STAT5A may account for the malignant effect of inorganic arsenic.
Conclusion:Low level, chronic arsenic exposure promotes malignant transformation in human epidermal keratinocytes, which is mediated through alteration of gene expression profiles directly. Information gained from our work is valuable for the direction of future experiments involving arsenic toxicity and skin cancer formation.
Conclusions
1. Low level, chronic arsenic exposure promotes malignant transformation in human epidermal keratinocytes (HaCaT).
2. The malignant population from chronic, low-level arsenic-treated HaCaT cells may develop from a rare population, which "the existence" of cancer stem cells (CSCs) with the capacity of self-renewal and potential differentiation. CD44v6may be a biomarker of arsenic-induced neoplastic transformation in human skin cells.
3. Arsenic promotes malignant transformation in HaCaT cells possibly involved in its activation of NF-κB and inactivation of P53.
4. The profile of gene expression between the arsenic-induced malignant transformation HaCaT cells and control cells were analyzed. Differential genes during transformation were involved in the regulation of cell proliferation, immune system process, cell development and cell adhesion. Wnt, MAPK, Jak-STAT, TGF-beta, NOTCH, PI-3K/AKT and NF-κB signaling pathway play an important role during arsenic-induced malignant transformation of HaCaT cells. Alteration of gene expression patterns and especially up-regulation of AKT2, MYC, DMD2, CCDN3, MAP3K14and down-regulation of JAK1, PTEN, ATM, STAT5A may account for the malignant effect of inorganic arsenic.
因此本研究以HaCaT细胞为研究对象,采用存在于自然界中对人体毒性较大的三价无机砷：亚砷酸钠(sodium arsenite, NaAsO2)进行长期(30代,约4个月)、低浓度诱导其恶性转化。结果发现,NaAsO2处理HaCaT细胞至25代后(约100天),以皮下注射方式将细胞注射进入到裸鼠左腋下,可见肿瘤的形成,肿瘤组织切片观察判定是鳞状细胞癌(squamous cell carcinoma, SCC),属于砷引起皮肤癌的一种类型。长期低水平砷暴露诱导成致瘤性的HaCaT细胞群中可能“存在的”为数不多的具有自我更新能力、分化潜能的癌干细胞(Cancer stem cells, CSCs),而CD44v6是其潜在的特异性分子标志物。肿瘤干细胞标志物CD44v6的活化可能与NaAsO2对NF-κ B的激活和对P53的抑制有关。
采用基因芯片技术、荧光定量PCR技术分析NaAsO2处理导致致瘤性转化的HaCaT细胞和同期配对的对照组HaCaT细胞的基因表达谱变化,通过生物信息学分析发现细胞增殖、免疫系统反应、细胞生长、细胞粘附运动等生物过程的失调或改变在长期低浓度NaAsO2诱导HaCaT细胞致瘤性转化过程中发挥重要作用。差异基因参与多条与肿瘤及癌干细胞密切相关的信号通路,如Wnt、MAPK、NOTCH、p53、cell cycle、apotosis、Jak-STAT、 TGF-beta、NF-κB、PI-3K/AKT等信号通路。与这些生物过程、信号通路密切相关的基因可能是砷致HaCaT细胞恶性转化过程中的关键因子,如鼠类胸腺瘤病毒(v-akt)同源体2/β-rac蛋白激酶(v-akt murine thymoma viral oncogene homolog2/protein kinase Bβ, AKT2),骨髓细胞瘤病毒同源的MYC原癌基因(v-myc myelocytomatosis viral oncogene homolog, MYC), MDM2癌基因(Mdm2p53binding protein homolog, murine double mimute2, MDM2),细胞周期蛋白D3(cyclin D3, CCND3),丝裂原活化蛋白激酶3K14(mitogen-activated protein kinase kinase kinase14, MAP3K14), Jak蛋白酪氨酸激酶-1(Janus kinase1, JAK1),基质金属蛋白酶-9(matrix metallopeptidase9, MMP9), PTEN抑癌基因(Phosphatase and tensin homolog deleted on chromosome ten, PTEN), ATM抑癌基因(Ataxia telangiectasia mutated, ATM),信号传导子及转录激活子5A(Signal transducer and activator of transcription5A, STAT5A), Rho相关蛋白激酶2(Rho-associated, coiled-coil containing protein kinase2, ROCK2)等。
第一章长期低浓度砷剂诱引角质形成细胞恶性转化的研究
为进一步了解无机砷的致癌性,因此利用0.05ppm(约0.4μM)NaAsO2处理人永生化角质形成细胞株(HaCaT)大约4个月,探讨暴露在长时间低浓度无机砷下的HaCaT细胞的生长情形,诱导HaCaT细胞发生致瘤性转化,为进一步探索、分析转化过程中肿瘤干细胞标志物表达变化和基因表达谱的变化提供基础。
HaCaT细胞常规培养于完全培养基DMEM。长时间细胞培养的做法是接种5×105个HaCaT细胞于100ml培养瓶中并且分别处理0,0.05ppm NaAsO2,当满2天时更换新的DMEM培养液,满4天时则进行隔代培养。总共隔代培养30代,约4个月中NaAsO2持续存在于DMEM培养液中。细胞培养期间,倒置显微镜下观察每代细胞形态的变化并拍照。并进行软琼脂克隆形成率(Colony-forming efficiency, CFE)等实验验证细胞的转化、应用MTT法测定转化细胞的增殖能力、流式细胞术(Flow Cytometry, FCM)检测转化细胞的细胞周期、并将恶性转化和同期配对传代的对照组HaCaT细胞注射于Balb/c裸鼠左侧腋窝皮下,观察肿瘤形成情况,并作组织切片、HE染色后进行组织病理学鉴定。
NaAsO2处理HaCaT细胞至25代后(约100天),以皮下注射方式将细胞打入裸鼠左腋下,可见肿瘤的形成。并且借由观察肿瘤组织切片判定是鳞状细胞癌,是砷引起皮肤癌的一种类型。经长期低浓度无机砷刺激的HaCaT细胞发生了致瘤性转化。此外,HaCaT细胞还有下列几项的变化：(1)软琼脂克隆形成实验表明NaAs02长期低浓度处理的细胞具有了非停泊性依赖生长的特性。(2)光镜下观察到细胞于培养瓶内长满时有较高的细胞密度,出现排列紊乱、重叠交叉生长现象,并出现多核巨细胞。(3)MTT检测结果表明长期低浓度NaAs02处理的HaCaT细胞的增殖能力较对照组细胞明显增强。(4)NaAsO2处理的HaCaT细胞较未处理的细胞有更多的细胞处于细胞周期的S、G2/M期,说明受NaAsO2处理细胞的增殖能力旺盛。
本部分实验成功建立了低水平NaAsO2慢性处理所致HaCaT细胞恶性转化模型,从而为进一步探讨砷化物所致细胞恶性转化分子机制提供了基础。
第二章长期低浓度砷剂诱引角质形成细胞恶性转化过程中肿瘤干细胞标志物的表达及意义
本部分旨在探讨肿瘤干细胞在砷致人角质形成细胞恶性转化中的作用及其影响因素,以期发现或揭示砷致皮肤癌过程中的肿瘤干细胞特异性标志物及相关信号转导通路。分别对第0,5,10,15,20,25,30代低浓度NaAsO2处理的HaCaT细胞和同期配对的对照组HaCaT细胞滴片进行荧光免疫组化(Immunofluorescence, IF)染色；同时提取上述不同时间点两组细胞的总蛋白,利用蛋白印迹(Western blotting, WB)等实验技术对可能存在的肿瘤干细胞标志物进行筛选,与其他检测指标进行相关分析。并分析其影响因素。
结果显示,长期低浓度NaAsO2处理的HaCaT细胞中,肿瘤干细胞标志物CD44v6蛋白含量有逐渐增加的表现；对照组CD44v6蛋白含量未发现明显变化。恶性转化的HaCaT细胞(第25代)其CD44v6蛋白含量比同期对照组HaCaT细胞(第25代)显著增加(P<0.05)。NaAsO2处理组HaCaT细胞在15代后,CD44v6阳性表达显著增加,定位于细胞膜,在25代和30代约有8%的阳性率。对CD44v6的表达与软琼脂克隆阳性率之间的关系进行分析,结果发现,r=0.949,P=0.01,两者呈正相关性。肿瘤干细胞标志物CD44v6表达变化可能与砷致NF-κB激活、P53抑制有关。
实验结果提示,长期低水平砷暴露所致皮肤损伤或癌组织中可能“存在的”为数不多的具有自我更新能力、分化潜能的癌干细胞,而CD44v6是其潜在的特异性分子标志物。肿瘤干细胞标志物CD44v6的活化可能与NaAsO2对NF-K B的激活和对P53的抑制有关。
第三章长期低浓度砷剂诱引角质形成细胞恶性转化的基因表达变化
本部分实验目的是探讨NaAsO2诱引人类皮肤细胞HaCaT恶性转化过程中基因表达谱的改变,分析差异基因的生物学意义,进而揭示在NaAsO2诱导HaCaT细胞致瘤性转化过程中可能起关键作用的生物学通路和分子,为理解砷暴露致皮肤癌发生的分子机制提供线索。实验方法：提取正常HaCaT细胞和转化HaCaT细胞的总RNA,应用高通量的基因芯片技术分析转化HaCaT细胞和正常对照HaCaT细胞基因表达谱的改变,运用实时定量PCR技术验证芯片的结果,并结合生物信息学分析对差异基因进行功能分类,同时探讨差异基因之间以及差异基因与其他基因之间可能的网络联系。
结果发现,恶性转化的HaCaT细胞和正常对照HaCaT细胞共发现2,871个表达差异基因(P<0.05时,差异倍数≥2),约占芯片探针总数的6.1%(2,871/44,000)。其中1,415个基因表达上调,1,456个基因表达下调。其中表达上调的基因包括鼠类胸腺瘤病毒(v-akt)同源体2/β-rac蛋白激酶(v-akt murine thymoma viral oncogene homolog2/protein kinase Bβ,AKT2),骨髓细胞瘤病毒同源的MYC原癌基因(v-myc myelocytomatosis viral oncogene homolog, MYC), MDM2癌基因(Mdm2p53binding protein homolog, murine double mimute2, MDM2),细胞周期蛋白D3(cyclin D3, CCND3),丝裂原活化蛋白激酶3K14(mitogen-activated protein kinase kinase kinase14, MAP3K14)等；表达下调的基因有Jak蛋白酪氨酸激酶-1(Janus kinase1, JAK1),基质金属蛋白酶-9(matrix metallopeptidase9, MMP9), PTEN抑癌基因(Phosphatase and tensin homolog deleted on chromosome ten, PTEN),ATM抑癌基因(Ataxia telangiectasia mutated, ATM),信号传导子及转录激活子5A(Signal transducer and activator of transcription5A,STAT5A), Rho相关蛋白激酶2(Rho-associated, coiled-coil containing protein kinase2, ROCK2)等。实时荧光定量PCR分析上述基因在两组细胞中的表达,进一步证实了芯片结果的可靠性。用Gene Ontology(GO)数据库将差异基因进行功能注释,结果发现差异基因产物主要参与细胞增殖(cell proliferation)、免疫系统反应(immune system process).细胞生长(cell development)、细胞粘附(cell adhesion)等与肿瘤发生、发展相关密切的功能调节。KEGG和Biocarta数据库分析差异基因之间的相互作用网络,结果发现差异基因参与多条信号通路,其中已知Wnt、MAPK、NOTCH、p53、cell cycle、apotosis、Jak-STAT、TGF-beta、 NF-κB、PI-3K/AKT等信号通路与肿瘤及癌干细胞密切相关。AKT2, JAK1, MMP9, MYC, PTEN, ATM, MDM2, STAT5A, CCND3, MAP3K14和ROCK2等与多条通路有关,可能在NaAsO2诱导HaCaT细胞的转化过程中发挥关键的作用。
以上结果提示：长期低浓度NaAsO2处理直接引起HaCaT细胞基因表达改变,砷暴露导致的细胞增殖、免疫调节、细胞粘附运动失衡或改变在其诱导HaCaT细胞致瘤性转化过程中可能发挥重要作用,Wnt、MAPK等多条信号通路参与砷诱导HaCaT细胞致瘤性转化过程,AKT2, JAK1, MMP9, MYC, PTEN, ATM, MDM2, STAT5A, CCND3, MAP3K14和ROCK2等基因可能是这一过程中的关键分子。
结论
1.人永生化角质形成细胞株HaCaT在长期低水平NaAsO2作用下发生了致瘤性转化。
2.长期低水平砷暴露诱导成致瘤性的HaCaT细胞群中可能“存在的”为数不多的具有自我更新能力、分化潜能的癌干细胞,而CD44v6是其潜在的特异性分子标志物。
3.肿瘤干细胞标志物CD44v6的活化可能与NaAsO2对NF-κB的激活和对P53的抑制有关。
4.分析了正常HaCaT细胞、转化HaCaT细胞的基因表达变化。在转化过程中发生改变的基因主要参与调节细胞增殖、免疫反应、细胞粘附运动等生物学过程；以及Wnt、MAPK、NOTCH、p53、cell cycle、apotosis、Jak-STAT、 TGF-beta、NF-kB、PI-3K/AKT等多条信号通路；AKT2, JAK1, MMP9, MYC, PTEN, ATM, MDM2, STAT5A, CCND3, MAP3K14和ROCK2等基因可能是转化过程中的关键分子。
Epidemiological studies from many countries and observed that chronic exposure to arsenic caused primarily skin cancer, but also lung cancer, urinary bladder cancer and liver cancer. However, inorganic arsenic fails to induce tumors in most laboratory animals. To explore the mechanisms of arsenic carcinogenesis, and to investigate the molecular mechanism of arsenic-induced skin cancer from cellular origin aspect may provide us some novel clues for explaining further development and progression of arsenic-induced skin cancer and for finding the valuable biomarkers of early diagnosis, prevention and treatment. The skin is a major target of arsenic exposure and one of the most sensitive tissues to chronic arsenic exposure. Thus, human skin keratinocytes are widely used for study of the arsenic toxicity. The human spontaneously immortalized skin keratinocytes (HaCaT) was originally derived from normal human adult skin, which maintains full epidermal differentiation capacity and is immortalized but nontumorigenic. It is an ideal model for the study of arsenic carcinogenicity.
Here, we repeatedly exposed the HaCaT cell line to an environmentally relevant level of arsenic (0.05ppm, about0.4u M) in vitro for about4months, determined the acquired cancer phenotype. Through a continuous exposure of HaCaT to non-toxic doses of sodium arsenite(0.05ppm) for several months,HaCaT cells became apparently tumorigenic in nude mice, pathological studiesof xenogratf tumor sections showed a highly undifferentiated, pleomorphicnature of tumors from arsenic-treated HaCaT cells, and the tumor testified assquamous cell carcinomas (SCC), a type of cancer that induced by arsenic inskin.
The present results suggest that the malignant population from chronic,low-level arsenic-treated HaCaT cells may develop from a rare population,which "the existence" of cancer stem cells (CSCs) with the capacity ofself-renewal and potential differentiation. CD44v6may be a biomarker ofarsenic-induced neoplastic transformation in human skin cells, and that arsenicpromotes malignant transformation in HaCaT cells through its activation ofNF-kB and inactivation of P53stimulated expression of CD44v6.
The changes of gene expression profile between the arsenic-treated cellsand passage-matched control cells was obtained through oligo microarraydetection and qPCR respectively. Bioinformaties analysis suggested that theimbalance between cell proliferation, immune system process, cell developmentand cell adhesion, etc. may play an important role in arsenic-induced neoplastictransformation of HaCaT cells. From the pathway comparison(Base on KEGGand Biocarta database), the differentially expressed genes involved in severalsignaling pathways that play an important role in cancer and cancer stem cells,such as Wnt, MAPK, Jak-STAT, TGF-beta, NOTCH, PI-3K/AKT and NF-kBsignaling pathway. Alteration of gene expression patterns and especiallyup-regulation of AKT2, MYC, DMD2, CCDN3, MAP3K14anddown-regulation of JAK1, PTEN, ATM, STAT5A may account for the malignanteffect of inorganic arsenic.
Part one Study of sodium arsenite-induced neoplastic transformation in human skin HaCaT cells
To explore the mechanisms of arsenic carcinogenesis, we have investigated the growth property and induced malignant transformation in spontaneously immortalized human skin keratinocytes (HaCaT), that were continuously exposed to non-toxic doses of arsenite (0.05ppm, about0.4μM) for approximately4months. This research was intended to provide a foundation for further work in analysis of cancer stem cells specific molecular marker and gene expression profile during arsenic-induced HaCaT cells malignant transformation.
The cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with10%fetal bovine serum (FBS), and antibiotics (100U/ml penicillin and100μg/ml streptomycin). For chronic exposure, cells were maintained continuously in a medium containing0.05ppm of NaAsO2for30passages (about4months). Morphological change was observed under light microscope or transmission electron microscope. We assessed colony forming efficiency (CFE) in soft agar every5passages (3weeks) to ascertain acquired malignant phenotype. Meanwhile, the proliferative ability of arsenic-treated HaCaT cells and passage-matched control cells were detected by MTT analysis, cell cycle was measured by flow cytometry (FCM). Once the soft agar colony assay suggested that arsenic-induced carcinogenic conversion had occurred, arsenic-treated and control cells were injected subcutaneously on the left axillary fossa of male Balb/c nude mice, animals were observed for tumor formation over a6-month period, and tumor tissue was examined by immunohistochemistry.
Through a continuous exposure of HaCaT to non-toxic doses of arsenite(0.05ppm) over25passages, HaCaT cells became apparently tumorigenic in nude mice, and the tumor testified as squamous cell carcinomas (SCC), a type of cancer that induced by arsenic in skin. In addition, we have observed the following changes caused by long term, low-level exposure to arsenite in HaCaT cells:(1) higher colony forming efficiency on soft agar;(2) higher cell density at confluence and exhibited morphological alterations with the frequent occurrence of giant multinuclear cells;(3) Higher capacity of proliferation; and (4) more population in S, G2/M phase.
These results suggested that HaCaT cells treated by chronic, low-level arsenite have neoplastic transformation. The transformed cells provided us basis for further study.
Part two The expression and significance of the cancer stem cell markers in arsenic-induced neoplastic transformation in human skin cells
To explore the effects of long-term, low concentration arsenic on cancer stem cell markers function in HaCaT cells. After treatment of Oppm,0.05ppm sodium arsenite for0passage,5passages,10passages,15passages,20passages,25passages and30passages. Western blotting and immunofluorescence staining were used to observe the expression of CD44v6, CD133, NF-κB and p53protein in arsenic-treated HaCaT cells and passage-matched control cells at different time points.
The research results show that the protein level of cancer stem cell marker, CD44v6was up-regulated after chronic, low level sodium arsenite administration while CD133protein level has no obvious change. CD44v6protein level increased steadily duration of arsenic treatment, and has significance difference from passage-matched control cells at25passages (P＜0.05). After treatment of0.05ppm sodium arsenite for15passages, CD44v6expression in arsenic-treated cells increased sharply, CD44v6immunoreactivity positive cells localized primarily in the membrane of some HaCaT cells, CD44v6positive ratio of CD44v6immunoreactivity positive cells is about8%at25and30passages of arsenic-treated cells. Moreover, the extent of CD44v6immunoreactivity in arsenic-treated cells was found to positively correlate with the cloning efficiency in soft agar (r=0.949, P=0.01). Arsenic exposure promoted abnormal expression of CD44v6possibly involved in its activation of NF-κB and inactivation of P53.
The present results suggested that the malignant population from chronic, low-level arsenic-treated HaCaT cells may develop from a rare population, which "the existence" of cancer stem cells (CSCs) with the capacity of self-renewal and potential differentiation. CD44v6may be a biomarker of arsenic-induced neoplastic transformation in human skin cells, and that arsenic promotes malignant transformation in human skin cells through its activation of NF-κB and the inactivation of P53.
Part three Arsenic promotes malignant transformation in human epidermal keratinocytes through alteration of gene expression patterns
To get more insight into the carcinogenic mechanism of arsenic action, we performed genome-wide expression profiling of arsenic-treated and untreated HaCaT cells using oligo microarrays (Agilent Whole Human Genome Oligo Microarray) that contain41,000genes. Data analysis included hierarchical clustering of differentially expressed genes, gene ontology enrichment analyses and pathway analysis. Eleven genes that involved in cancer were selected for further evaluation by quantitative RT-PCR (qPCR).
Gene expression profile analysis revealed that2,871were differentially expressed between malignant HaCaT cells and normal HaCaT cells. Of these,1,415were significantly up-regulated and1,456were statistically significantly down-regulated in malignant HaCaT cells. Up-regulated genes included AKT2(v-akt murine thymoma viral oncogene homolog2/protein kinase Bβ), MYC(v-myc myelocytomatosis viral oncogene homolog), MDM2(Mdm2p53binding protein homolog, murine double mimute2), CCND3(cyclin D3), MAP3K14(mitogen-activated protein kinase kinase kinase14), etc. Down-regulated genes had Jakl (Janus kinase1), MMP9(matrix metallopeptidase9), PTEN (Phosphatase and tensin homolog deleted on chromosome ten), ATM (Ataxia telangiectasia mutated), STAT5A(Signal transducer and activator of transcription5A), ROCK2(Rho-associated, coiled-coil containing protein kinase2),etc. The differentially expressed genes with functions that include cell proliferation, immune system process, cell development and cell adhesion, and involved in several signaling pathways that play an important role in cancer and cancer stem cells, such as Wnt, MAPK, Jak-STAT, TGF-beta, NOTCH, PI-3K/AKT and NF-κB signaling pathway. Alteration of gene expression patterns and especially up-regulation of AKT2, MYC, DMD2, CCDN3, MAP3K14and down-regulation of JAK1, PTEN, ATM, STAT5A may account for the malignant effect of inorganic arsenic.
Conclusion:Low level, chronic arsenic exposure promotes malignant transformation in human epidermal keratinocytes, which is mediated through alteration of gene expression profiles directly. Information gained from our work is valuable for the direction of future experiments involving arsenic toxicity and skin cancer formation.
Conclusions
1. Low level, chronic arsenic exposure promotes malignant transformation in human epidermal keratinocytes (HaCaT).
2. The malignant population from chronic, low-level arsenic-treated HaCaT cells may develop from a rare population, which "the existence" of cancer stem cells (CSCs) with the capacity of self-renewal and potential differentiation. CD44v6may be a biomarker of arsenic-induced neoplastic transformation in human skin cells.
3. Arsenic promotes malignant transformation in HaCaT cells possibly involved in its activation of NF-κB and inactivation of P53.
4. The profile of gene expression between the arsenic-induced malignant transformation HaCaT cells and control cells were analyzed. Differential genes during transformation were involved in the regulation of cell proliferation, immune system process, cell development and cell adhesion. Wnt, MAPK, Jak-STAT, TGF-beta, NOTCH, PI-3K/AKT and NF-κB signaling pathway play an important role during arsenic-induced malignant transformation of HaCaT cells. Alteration of gene expression patterns and especially up-regulation of AKT2, MYC, DMD2, CCDN3, MAP3K14and down-regulation of JAK1, PTEN, ATM, STAT5A may account for the malignant effect of inorganic arsenic.
引文
1. Higginson J, DeVita VT Jr.IARC monographs on the evaluation of carcinogenic risk of chemicals to humans. Am Ind Hyg Assoc J.1980;41(5):A26, A28, A30 passim.
2. McLellan F. Arsenic contamination affects millions in Bangladesh. Lancet. 2002; 359(9312):1127.
3. Alam MG, Snow ET, Tanaka A. Arsenic and heavy metal contamination of vegetables grown in Samta village, Bangladesh. Sci Total Environ.2003; 308(1-3):83-96.
4. Matschullat J. Arsenic in the geosphere-a review. Sci Total Environ. 2000;249(1-3):297-312.
5. Sheehy JW, Jones JH. Assessment of arsenic exposures and controls in gallium arsenide production. Am Ind Hyg Assoc J.1993;54:61-69.
6. Soucy NV, Ihnat MA, Kamat CD,et al. Arsenic stimulates angiogenesis and tumorigenesis in vivo. Toxicol Sci.2003; 76(2):271-279.
7. Sun G, Li X,Pi J, et al. Current research problems of chronic arsenieosis in China. J Heaith Popul Nutr.2006; 24(2):176-181.
8. Alonso FT, Garmendia ML, Bogado ME. Increased skin cancer mortality in Chile beyond the effect of ageing:Temporal analysis 1990 to 2005. Acta Derm Venereol.2010;90(2):141-146.
9. Celik I, Gallicchio L, Boyd K, Lam TK, Matanoski G, Tao X, et al. Arsenic in drinking water and lung cancer:a systematic review. Environ Res. 2008;108(1):48-55.
10. Chen CL, Chiou HY, Hsu LI, Hsueh YM, Wu MM, Wang YH, et al. Arsenic in drinking water and risk of urinary tract cancer:a follow-up study from northeastern Taiwan. Cancer Epidemiol Biomarkers Prev.2010; 19(1):101-110.
11. Meliker JR, Slotnick MJ, AvRuskin GA, Schottenfeld D, Jacquez GM, Wilson ML, et al. Lifetime exposure to arsenic in drinking water and bladder cancer:a population-based case-control study in Michigan, USA. Cancer Causes Control.2010;21(5):745-757.
12. Morales KH, Ryan L, Kuo TL, Wu MM, Chen CJ. Risk of internal cancers from arsenic in drinking water. Environ Health Perspect.2000;108(7):655-661.
13. Smith AH, Hopenhayn-Rich C, Bates MN, Goeden HM, Hertz-Picciotto I, Duggan HM, et al. Cancer risks from arsenic in drinking water. Environ Health Perspect.1992;97:259-267.
14. IARC. "Some drinking-water disinfectants and contaminants, including arsenci, Monographs on chloramine, chloral and chloral hydrate, dichloroacetic acid and 3-chloro-4-(dichloromethly)- 5-hydoroxy-2(5H)-furanone". International Agency for Research on Cancer (IARC) Monographs on the Evaluation of Carcinogenic Risks to Humans.2004:269-477.
15. Chen CJ, Wang SL, Chiou JM, et al, Arsenic and diabetes and hypertension in human populations:a review. Toxicol Appl Pharmacol.2007;222(3):298-304.
16. Tseng GH, Tai TY, Chong CK, et al. Long-term arsenic exposure and incidence of noninsulin dependent diabetes mellitus:A cohort study in arsenicosis hyperendemic villages in Taiwan. Environ Health Perspect. 2000; 108:847-851.
17. Tondel M, Rahmen M,Magnuson A, et al. The relationship of arsenic levels in drinking water and the prevalence rate of skin lesions in Bangladesh.Environ Health Perspect.1999; 107:727-729.
18. Smith AH, Hopenhayn-Rich C, Bates MN,et al. Cancer risks from arsenic in drinking water. Environ Health Perspect.1992;97:259-267.
19. Pi J, Diwan BA, Sun Y, et al. Arsenic-induced malignant transformation of human keratinocytes:involvement of Nrf2. Free Radic Biol Med.2008; 45(5): 651-658.
20. Pei B, Wang S, Guo X, et al. Arsenite-induced germline apoptosis through a MAPK-dependent,p53-independent pathway in Caenorhabditis elegans. Chem Res Toxicol.2008;21(8):1530-1535.
21. Bernstam L, Nriagu J. Molecular aspects of arsenic stress. J Toxicol Environ Health B Crit Rev.2000; 3(4):293-322.
22. Polyak K, Hahn WC. Roots and stems:stem cells in cancer. Nat.Med.2005; 11:296-300.
23. Singh SK, Clarke ID, Hide T, et al. Cancer stem cells in nervous system tumors. Oncogene.2004; 23(43):7267-7273.
24. Singh SK, Clarke ID, Terasaki M, et al. Identification of acancer stem cell in human brain tumors. Cancer Res.2003; 63(18):5821-5828.
25. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature.2004; 432(7015):396-401.
26. Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA.2003; 100(25):15178-15183.
27. Richardson D, Robson CN, Lang SH, et al. CD 133, a novel marker for human prostatic epithelial stem cells. J Cell Sci.2004; 117 (Pt 16):3539-3545.
28. Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res.2005; 65(23): 10946-10951.
29. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA.2003; 100(7):3983-3988.
30. Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65(13):5506-5511.
31. Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell.2005; 8(4):323-335.
32. Perez-Losada J, Balmain A. Stem-cell hierarchy in skin cancer. Nat Rev Cancer.2003; 3(6):434-443.
33. Seigel GM, Campbell LM, Narayan M, et al. Cancer stem cell characteristics in retinoblastoma. Mol Vis.2005; 11:729-737.
34. Li C, Heidt DG, Mollenberg N, et al. Identification of pancreatic cancer stem cells. Pancreas.2005; 31(4):452.
35. Fiegel HC, Gluer S, Roth B, et al. Stem-like cells in human hepatoblastoma. J Histochem Cytochem.2004; 52(11):1495-1501.
36. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science.2004; 306(5701):1568-1571.
37. Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer.Cell.2005; 121(6):823-835.
38. Setoguchi T, Taga T, Kondo T. Cancer stem cells persist in many cancer cell lines. Cell Cycle.2004; 3(4):414-415.
39. Patrawala L, Calhoun T, Schneider-Broussard R, et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2-cancer cells are similarly tumorigenic. Cancer Res.2005; 65(14): 6207-6219.
40. Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA.2004; 101(3):781-786.
41. Yuan Li,Min Ling,Yuan Xu, et al. The Repressive Effect of NF-kB on p53 by Mot-2 Is Involved in Human Keratinocyte Transformation Induced by Low Levels of Arsenite. Toxicol sci.2010; 116(1):174-182.
42. Ouyang W, Luo W, Zhang D, et al. PI-3K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation. Environ Health Perspect.2008; 116(1):1-6.
43. Patterson TJ, Reznikova TV, Phillips MA, et al. Arsenite maintains germinative state in cultured human epidermal cells. Toxicol Appl Pharmacol. 2005;207:69-77.
44. Patterson TJ, Rice RH. Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. Toxicol Appl Pharmacol.2007; 221:119-128.
45. Waalkes MP, Liu J, Germolec DR, et al. Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics. Cancer Res.2008; 68,8278-8285.
46. Tokar EJ, Diwan BA, Waalkes MP. Arsenic exposure transforms human stem/progenitor cells into a cancer stem cell-like phenotype. Environ Health Perspect.2010;118:108-115.
47. Tokar EJ, Qu W, Liu J, et al. Arsenic-specific stem cell selection during malignant transformation. J Natl Cancer Inst.2010; 102,638-649.
48. Reya T, Morrison SJ, Clarke MF, et al. Stem cells,cancer, and cancer stem cells.Nature.2001;414:105-111.
49. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer.2003;3:895-902.
50. Lobo NA, Shimono Y, Qian D, et al. The biology of cancer stem cells. Annu Rev Cell Dev Biol.2007; 23:675-699.
51. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumors:accumulating evidence and unresolved questions. Nat Rev Cancer.2008; 8:755-768.
52. Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature.2006;442:818-822.
1. IARC. "Some drinking-water disinfectants and contaminants, including arsenci, Monographs on chloramine, chloral and chloral hydrate, dichloroacetic acid and 3-chloro-4-(dichloromethly)- 5-hydoroxy-2(5H)-furanone". International Agency for Research on Cancer (IARC) Monographs on the Evaluation of Carcinogenic Risks to Humans.2004:269-477.
2. Alonso FT, Garmendia ML, Bogado ME. Increased skin cancer mortality in Chile beyond the effect of ageing:Temporal analysis 1990 to 2005. Acta Derm Venereol.2010;90(2):141-146.
3. Celik I, Gallicchio L, Boyd K, et al. Arsenic in drinking water and lung cancer: a systematic review. Environ Res.2008;108(1):48-55.
4. Chen CL, Chiou HY, Hsu LI, et al. Arsenic in drinking water and risk of urinary tract cancer:a follow-up study from northeastern Taiwan. Cancer Epidemiol Biomarkers Prev.2010; 19(1):101-110.
5. Meliker JR, Slotnick MJ, AvRuskin GA, et al. Lifetime exposure to arsenic in drinking water and bladder cancer:a population-based case-control study in Michigan, USA. Cancer Causes Control.2010;21(5):745-757.
6. Morales KH, Ryan L, Kuo TL,et al. Risk of internal cancers from arsenic in drinking water. Environ Health Perspect.2000;108(7):655-661.
7. Smith AH, Hopenhayn-Rich C, Bates MN, et al. Cancer risks from arsenic in drinking water. Environ Health Perspect.1992;97:259-267.
8.Pi.J, Diwan. BA, Sun Y, et al. Arsenic-induced malignant transformation of human keratinocytes:involvement of Nrf2. Free Radic Biol Med.2008;45(5): 651-658.
9. Pei B, Wang S, Guo X, et al. Arsenite-induced germline apoptosis through a MAPK-dependent,p53-independent pathway in Caenorhabditis elegans. Chem Res Toxicol.2008;21(8):1530-1535.
10. Bernstam L, Nriagu J. Molecular aspects of arsenic stress. J Toxicol Environ Health B Crit Rev.2000;3(4):293-322.
11. Marinissen MJ, Sevritja JM, Oeffmrnnas S, et al. Thrombin Portease-ativated receptor singals through Gq-and G13-initiated MAPK cascades regulating c-Jun expression to induce cell trnasofmration. J Biol Chem.2003;278(47):46814-46825.
12. Bridge JW, Benofdr DJ, Hubbdar SA. The design and use of invro toxicity tests. In:RTumer(Ed), Animals in Scientific Research:An effective substitute for man? Maemillina,London.1983:47.
13.刘国谦.细胞毒理学.北京.军事医学科学出版社.2001：287-291.
14. Ouyang W, Luo W, Zhang D, et al. PI-3K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation. Environ Health Perspect.2008; 116(1):1-6.
15. Boukamp P, Petrussevska RT, Breitkreutz D, et al. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol. 1988;106(3):761-771.
16. Pinlaor S, Ma N, Hiraku Y, et al. Repeated infection with Opisthorchis viverrini induces accumulation of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanine in the bile duct of hamsters via inducible nitric oxide synthase. Carcinogenesis.2004;25(8):1535-1542.
17. Bodwell JE, Kingsley LA, Hamilton JW. Arsenic at very low concentrations alters glucocorticoid receptor (GR)-mediated gene activation but not GR-mediated gene repression:complex dose-response effects are closely correlated with levels of activated GR and require a functional GR DNA binding domain. Chem Res Toxicol.2004; 17(8):1064-1076.
18. He XQ, Chen R, Yang P, et al. Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK1/2 in human embryo lung fibroblast cells. Toxicol Appl Pharmacol. 2007;220(1):18-24.
19. Shen S, Lee J, Weinfeld M, Le XC. Attenuation of DNA damage-induced p53 expression by arsenic:a possible mechanism for arsenic co-carcinogenesis. Mol Carcinog.2008 Jul;47(7):508-518.
20. Wen G, Calaf GM, Partridge MA, et al. Neoplastic transformation of human small airway epithelial cells induced by arsenic. Mol Med.2008;14(1-2):2-10.
21. Zhao CQ, Young MR, Diwan BA, et al. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci USA.1997; 94(20):10907-10912.
22. Romach EH, Zhao CQ, Del Razo LM, et al. Studies on the mechanisms of arsenic-induced self tolerance developed in liver epithelial cells through continuous low-level arsenite exposure. Toxicol Sci.2000;54(2):500-508.
23. Sens DA, Park S, Gurel V, et al. Inorganic cadmium- and arsenite-induced malignant transformation of human bladder urothelial cells. Toxicol Sci.2004; 79(1):56-63.
24.胡宇,金喜梅,王国荃,等.砷诱导NIH3T3细胞转化模型的建立.新疆医科大学学报.2004；27(1)：1-5.
25. Wen G, Calaf GM, Partridge MA, et al. Neoplastic transformation of human small airway epithelial cells induced by arsenic. Mol Med.2008; 14(1-2):2-10.
26. Li Y, Ling M, Xu Y, et al. The Repressive Effect of NF-kB on p53 by Mot-2 Is Involved in Human Keratinocyte Transformation Induced by Low Levels of Arsenite. Toxicol sci.2010; 116(1):174-182.
27. Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology.4th edition.New York:W. H. Freeman; 2000.
28. Gildea JJ, Golden WL, Harding MA, et al.Genetic and phenotypic changes associated with the acquisition of tumorigenicity in human bladder cancer. Genes Chromosomes Cancer.2000;27(3):252-263.
29. Funk JO, Kind P. Cell cycle control, genetic instability and cancer. Hautarzt. 1997;48(3):157-165.
30. Hakem R. DNA-damage repair; the good, the bad, and the ugly. Embo J. 2008.27(4):589-605.
31. Londhe VA, Nguyen HT, Jeng JM, et al. NF-κB induces lung maturation during mouse lung morphogenesis. Dev Dyn.2008; 237(2):328-338.
32. Halazonetis TD, Gorgoulis VG, Bartek J. An oncogene-induced DNA damage model for cancer development. Science.2008;319(5868):1352-1355.
33.金银龙,陈昌杰,陈西平,等.生活饮用水卫生标准GB5749-2006.中国标准出版社.2007.
34. US EPA. Drinking Water Standards and Health Advisories. Winter 2004.
1. International Agency for Researchon Cancer(1ARC). Monographs on the evaluation of the carcinogenic risk of chemicals to man overall evaluation of carcinogenicity:all update of IARC monographs 1 to 42:arsenic and arsenic compounds. France:IARC,1987:100-106.
2. Polyak K, Hahn WC. Roots and stems:stem cells in cancer. Nat.Med.2005; 11:296-300.
3. Singh SK, Clarke ID, Hide T, et al. Cancer stem cells in nervous system tumors. Oncogene.2004; 23(43):7267-7273.
4. Singh SK, Clarke ID, Terasaki M, et al. Identification of acancer stem cell in human brain tumors. Cancer Res.2003; 63(18):5821-5828.
5. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature.2004; 432(7015):396-401.
6. Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA.2003; 100(25):15178-15183.
7. Richardson D, Robson CN, Lang SH, et al. CD 133, a novel marker for human prostatic epithelial stem cells. J Cell Sci.2004; 117 (Pt 16):3539-3545.
8. Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res.2005; 65(23):10946-10951.
9. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA.2003; 100(7):3983-3988.
10. Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65(13):5506-5511.
11. Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell.2005; 8(4):323-335.
12. Perez-Losada J, Balmain A. Stem-cell hierarchy in skin cancer. Nat Rev Cancer.2003; 3(6):434-443.
13. Seigel GM, Campbell LM, Narayan M, et al. Cancer stem cell characteristics in retinoblastoma. Mol Vis.2005; 11:729-737.
14. Li C, Heidt DG, Mollenberg N, et al. Identification of pancreatic cancer stem cells. Pancreas.2005; 31(4):452.
15. Fiegel HC, Gluer S, Roth B, et al. Stem-like cells in human hepatoblastoma. J Histochem Cytochem.2004; 52(11):1495-1501.
16. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science.2004; 306(5701):1568-1571.
17. Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer.Cell.2005; 121(6):823-835.
18. Setoguchi T, Taga T, Kondo T. Cancer stem cells persist in many cancer cell lines. Cell Cycle.2004; 3(4):414-415.
19. Patrawala L, Calhoun T, Schneider-Broussard R, et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2 —ancer cells are similarly tumorigenic. Cancer Res.2005; 65(14):6207-6219.
20. Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA.2004; 101(3):781-786.
21. Patterson TJ, Reznikova TV, Phillips MA, et al. Arsenite maintains germinative state in cultured human epidermal cells. Toxicol Appl Pharmacol. 2005;207:69-77.
22. Patterson TJ, Rice RH. Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. Toxicol Appl Pharmacol.2007; 221:119-128.
23. Waalkes MP, Liu J, Germolec DR, et al. Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics. Cancer Res.2008; 68,8278-8285.
24. Tokar EJ, Diwan BA, Waalkes MP. Arsenic exposure transforms human stem/progenitor cells into a cancer stem cell-like phenotype. Environ Health Perspect.2010; 118:108-115.
25. Tokar EJ, Qu W, Liu J, et al. Arsenic-specific stem cell selection during malignant transformation. J Natl Cancer Inst.2010; 102,638-649.
26. Omran OM, Ata HS. CD44s and CD44v6 in diagnosis and prognosis of human bladder cancer. Ultrastruct Pathol.2012;36(3):145-152.
27. Gunthert U, Hofinann M, Rudy W, et al. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 1991;65(1):13-24.
28. Zhou ZJ, Dai Z, Zhou SL, et al. Overexpression of HnRNP A1 promotes tumor invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma. Int J Cancer.2013; 132(5):1080-1089.
29. Gun BD, Bahadir B, Bektas S, et al. Clinicopathological significance of fascin and CD44v6 expression in endometrioid carcinoma. Diagn Pathol. 2012;7(1):80.
30. Goodison S, Urquidi V, Tarin D. CD44 cell adhesion molecules. Molecular Pathology.1999; 52(4):189-196.
31. Turley EA, Noble PW, Bourguignon LY. Signaling properties of hyaluronan receptors. J Biol Chem.2002;277(7):4589-4592.
32. Welsh CF, Zhu D, Bourguignon LY. Interaction of CD44 variant isoforms with hyaluronic acid and the cytoskeleton in human prostate cancer cells. J Cell Physiol.1995;164(3):605-612.
33. Matsumura Y, Hanbury D, Smith J,et al. Non-invasive detection of malignancy by identification of unusual CD44 gene activity in exfoliated cancer cells.BMJ.1994;308(6929):619-624.
34. Peng J, Lu JJ, Zhu J, et al. Prediction of Treatment Outcome by CD44v6 After Total Mesorectal Excision in Locally Advanced Rectal Cancer. The Cancer Journal.2008;14(1):54-61.
35.张增锋,韦敏怡,李德进,等.鼻咽癌中CD44v6和nm-23H1的表达与淋巴 结转移的关系.广西医科大学学报.2001；18(4)：473.
36. Wang DR, Chen GY, Liu XL, et al. CD44v6 in peripheral blood and bone marrow of patients with gastric cancer as micro-metastasis. World J Gastroenterol.2006;12(1):36-42.
37. Saito H, Tsujiiani S, Katano K, et al. Serum concentration of CD44 variant 6 and its relation to prognosis in patients with gastric carcinoma. Cancer.1998; 83(6):1094-1101.
38. Lamb RE, Hennigan RF, Tumbull UK,et al. AP-1-mediated invasion requires increased expression of the hyaluronan receptor CD44. Mol Cell Biol.1997;17(2):963-976.
39. Colnot DR, Quak JJ, Roos JC,et al. Phase I therapy study of 186Re-labeled chimeric monoclonal antibody U36 in patients with squamous cell carcinoma of the head and neck. J Nucl Med.2000;41(12):1999-2010.
40. Heider KH, Kuthan H, Stehle G, et al. CD44v6:a target for antibody-based cancer therapy. Cancer Immunol Immunother.2004; 53(7):567-579.
41. Halazonetis TD, Gorgoulis VG, Bartek J. An oncogene-induced DNA damage model for cancer development. Science.2008;319(5868):1352-1355.
42. Protrka Z, Arsenijevic S, Dimitrijevic A, et al. Co-overexpression of bcl-2 and c-myc in uterine cervix carcinomas and premalignant lesions. Eur J Histochem.2011;55(1):e8.
43. Konstantakou EG, Voutsinas GE, Karkoulis PK. Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses. Int J Oncol.2009; 35(2):401-416.
44. Lim do Y, Park JH. Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. Am J Physiol Gastrointest Liver Physiol.2009;296(5):G1060-1068.
45. Aylon Y, Oren M. Living with p53, dying of p53. Cell.2007; 130(4):597-600.
46. Kastan MB. Wild-type p53:tumors can't stand it. Cell.2007;128(5):837-840.
47. De Chaudhuri S, Kundu M, Banerjee M,et al. Arsenic-induced health effects and genetic damage in keratotic individuals:involvement of p53 arginine variant and chromosomal aberrations in arsenic susceptibility. Mutat Res. 2008;659(1-2):118-125.
48. Shen S, Lee J, Weinfeld M, et al. Attenuation of DNA damage-induced p53 expression by arsenic:a possible mechanism for arsenic co-carcinogenesis. Mol Carcinog.2008; 47(7):508-518.
49. Huang Y, Zhang J, McHenry KT,et al. Induction of cytoplasmic accumulation of p53:a mechanism for low levels of arsenic exposure to predispose cells for malignant transformation.Cancer Res.2008;68(22): 9131-9136.
50. Stommel JM, Wahl GM. Accelerated MDM2 auto-degradation induced by DNA-damage is required for p53 activation. Embo J.2004; 23(7):1547-1556.
51. Hamadeh HK, Vargas M, Lee E,et al. Arsenic disrupts cellular levels of p53 and mdm2:a potential mechanism of carcinogenesis. Biochem Biophys Res Commun.1999;263(2):446-449.
52. Tergaonkar V, Perkins ND. p53 and NF-kappaB crosstalk:IKKalpha tips the balance. Mol Cell.2007;26(2):158-159.
53. Karin M, Cao Y, Greten FR, et al.NF-kappaB in cancer:from innocent bystander to major culprit.Nat Rev Cancer.2002;2(4):301-310.
54. Sakon S, Xue X, Takekawa M, et al. NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. Embo J.2003;22(15):3898-3909.
55. Karin M. NF-kappaB and cancer:mechanisms and targets. Mol Carcinog. 2006;45(6):355-361.
56. Jeong SJ, Pise-Masison CA, Radonovich MF, et al. A novel NF-kappaB pathway involving IKKbeta and p65/RelA Ser-536 phosphorylation results in p53 Inhibition in the absence of NF-kappaB transcriptional activity. J Biol Chem. 2005; 280(11):10326-10332.
57. Campo GM, Avenoso A, Campo S, et al. NF-kB and caspases are involved in the hyaluronan and chondroitin-4-sulphate-exerted antioxidant effect in fibroblast cultures exposed to oxidative stress. J Appl Toxicol.2008; 28(4): 509-517.
58. Huang WC, Ju TK, Hung MC, et al. Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Mol Cell.2007;26(1):75-87.
59. Sherine T, Seema S, Conrad T, et al. Kindlin-2 Expression in Arsenite and Cadmium Transformed Bladder Cancer Cell Lines and in Archival Specimens of Human Bladder Cancer. Urology.2011; 77(6):1507.el-1507.e7.
60. Serkan Sertel, Margaret Tome, Margaret M. Briehl, Judith Bauer, Kai Hock, et al. Factors Determining Sensitivity and Resistance of Tumor Cells to Arsenic Trioxide. PLoS One.2012;7(5):e35584.
61. Udensi UK, Cohly HH, Graham-Evans BE, et al. Aberrantly expressed Genes in HacaT Keratinocytes chronically exposed to Arsenic Trioxide. Biomarker Insights.2011; 6:7-16.
62. Bae DS, Handa RJ, Yang RS, et al. Gene Expression Patterns as Potential Molecular Biomarkers for Malignant Transformation in Human Keratinocytes Treated with MNNG, Arsenic, or a Metal Mixture. Toxicol sci.2003;74:32-42.
63. Bae DS, Hanneman WH, Yang RS, et al. Characterization of gene expression changes associated with MNNG, arsenic, or metal mixture treatment in human keratinocytes:application of cDNA microarray technology. Environ Health Perspect.2002; 110 Suppl 6:931-941.
1. Powell CL,Kosyk O,Bradford BU,et al. Temporal correlation of Pathology and DNA damage with gene expression in a choline-deficient model of rat liver injury. Hepatology.2005;42(5):1137-1147.
2. Kremer A, Schneider R, Terstappen GC. A bioinformatics perspective on proteomics:data storage, analysis, and integration. Biosci Rep.2005; 25(1-2): 95-106.
3. Waters MD, Fostel JM. Toxicogenomics and systems toxicology:aims and prospects. Nat Rev Genet.2004; 5:936-948.
4. Argos M, Kibriya MG, Parvez F, et al. Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev.2006; 15:1367-1375.
5. States JC, Singh AV, Knudsen TB, et al. Prenatal Arsenic Exposure Alters Gene Expression in the Adult Liver to a Proinflammatory State Contributing to Accelerated Atherosclerosis. PLoS ONE.2012; 7(6):e38713.
6. Liu J, Xie Y, Ducharme DM, et al. Global gene expression associated with hepatocarcinogenesis in adult male mice induced by in utero arsenic exposure. Environ Health Perspect.2006; 114:404-411.
7. Sasaki A, Oshima Y, Fujimura A. An approach to elucidate potential mechanism of renal toxicity of arsenic trioxide. Exp Hematol.2007; 35:252-262.
8. Posey T, Weng T, Chen Z, et al. Arsenic-induced changes in the gene expression of lung epithelial L2 cells:implications in carcinogenesis. BMC Genomics.2008; 9:115.
9. Su PF, Hu YJ, Ho IC, et al. Distinct gene expression profiles in immortalized human urothelial cells exposed to inorganic arsenite and its methylated trivalent metabolites. Environ Health Perspect.2006; 114:394-403.
10. Wang XJ, Yang J, Cang H,et al. Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Research.2005; 15(7):511-522.
11. Komissarova EV, Li P, Uddin AN et al. Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite:Identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol.2008; 226(2):199-205.
12. Sertel S, Tome M, Briehl MM, et al. Factors Determining Sensitivity and Resistance of Tumor Cells to Arsenic Trioxide. PLoS One.2012;7(5):e35584.
13. George Casella, Roger L. Berger. Statistic inference. Chapter2. Proc Natl Acad Sci USA.
14. Tusher VG, Tibshirani R, Chu G.Significance analysis of microarrays applied to the ionizing radiation response.2001;98(9):5116-5121.
15. Cox TF, Cox MAA. Multidimensional scaling. Chapman and Hall.1994.
16. JL Rodgers, WA Nicewander. Thirteen ways to look at the correlation coefficient. The American Statistician.1988; 42(1):59-66.
17. Stephen M. Stigler. Francis Galton's Account of the Invention of Correlation. Statist. Sci.1989;4(2):73-79.
18. Anderberg,Michael R. Cluster Analysis for Applications. academic press. 1973;New York.
19. Oliver Dreesen, Ali H. Bri vanlou. Signaling Pathways in Cancer and Embryonic Stem Cells. Stem Cell Rev.2007;3(1):7-17.
20. DurrR,CaselmannWH.Carcinogenesis of Primary liver malignaneies. Langenbecks Aieh Surg.2000;385(3):154-161.
21. Bodwell JE, Kingsley LA, Hamilton JW. Arsenic at very low concentrations alters glucocorticoid receptor (GR)-mediated gene activation but not GR-mediated gene repression:complex dose-response effects are closely correlated with levels of activated GR and require a functional GR DNA binding domain. Chem Res Toxicol.2004; 17(8):1064-1076.
22.He XQ, Chen R, Yang P,et al. Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK1/2 in human embryo lung fibroblast cells. Toxicol Appl Pharmacol.2007;220(1):18-24.
23. Shen S, Lee J, Weinfeld M, et al. Attenuation of DNA damage-induced p53 expression by arsenic:a possible mechanism for arsenic co-carcinogenesis. Mol Carcinog.2008;47(7):508-518.
24. Wen G, Calaf GM, Partridge MA, et al. Neoplastic transformation of human small airway epithelial cells induced by arsenic. Mol Med.2008;14(1-2):2-10.
25. NRC. Arsenic in the drinking water. National Research Council, National Academy; Washington, DC.2001:1-244.
26.孔贵范,曲龙.砷的分子作用机制研究现状与展望.中国地方病学杂志.2003；22：13-16.
27. Douglas Hanahan, Robert A. Weinberg. Hallmarks of Cancer:The Next Generation. Cell.2011;144(5):646-674.
28. Bozzuto G, Ruggieri P, Molinari A. Molecular aspects of tumor cell migration and invasion. Ann Ist Super Sanita.2010; 46(1):66-80.
29. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta.2013;1830(2):2481-2495.
30. Fry RC, Navasumrit P, Valiathan C, et al. Activation of inflammation/NF-KB signaling in infants born to arsenic-exposed mothers. PLoS Genet.2007,3:e207.
31. Maria A, Muhammad G. Kibriya, et al. Gene Expression Profiles in Peripheral Lymphocytes by Arsenic Exposure and Skin Lesion Status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006;15:1367-1375.
32. Dower SK, Qwarnstrom EE, Page RC, et al. Biology of the interleukin-1 receptor. J Invest Dermatol.1990;94:68-73S.
33. Labow M, Shuster D, Zetterstrom M, et al. Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice.J Immunol. 1997;159:2452-2461.
34. Takami Y, Motoki T, Yamamoto I, et al. Synergistic induction of hepatocyte growth factor in human skin fibroblasts by the inflammatory cytokines interleukin-1 and interferong. Biochem Biophys Res Commun. 2005;327:212-217.
35. Liu Q, Zhang H, Smeester L, et al. The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med. Genomics.2010; 3:37.
36. Mo J, Xia Y, Wade TJ. Altered Gene Expression by Low-Dose Arsenic Exposure in Humans and Cultured Cardiomyocytes:Assessment by Real-Time PCR Arrays. Int J Environ Res Public Health.2011; 8:2090-2108.
37. Menendez D, Mora G, Salazar AM,et al. ATM status confers sensitivity to arsenic cytotoxic effects. Mutagenesis.2001; 16:443-844.
38. Yoda A, Toyoshima K, Watanabe Y, et al. Arsenic Trioxide Augments Chk2/p53-mediated Apoptosis by Inhibiting Oncogenic Wipl Phosphatase. J Biol Chem.2008; 283(27):18969-18979.
39.Takahashi M, Ota A, Karnan S, et al. Arsenic trioxide prevents nitric oxide production in lipopolysaccharide -stimulated RAW 264.7 by inhibiting a TRIF-dependent pathway. Cancer Sci.2012;doi:10.1111/cas.12053.
40. Xia J, Li YJ, Yang QL, et al. Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer. Int. J. Mol. Sci.2012; 13:9627-9641.
41. Lau A, Whitman SA, Jaramillo MC, et al. Arsenic-Mediated Activation of the Nrf2-Keapl Antioxidant Pathway. J Biochem Mol Toxicol.2013; 27(2): 99-105.
42. Zhang Z, Wang X, Cheng S, et al. Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/β-catenin pathway in human colorectal adenocarcinoma DLD1 cells. Toxicol Appl Pharmacol.2011; 256(2):114-121.
43. Hayashi T, Hideshima T, Akiyama M, et al. Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow micro-environment. Mol Cancer Ther.2002; 1:851-860.
44. Qu W, Bortner CD, Sakurai T,et al. Acquisition of apoptotic resistance in arsenic-induced malignant transformation:role of the JNK signal transduction pathway. Carcinogenesis.2002;23(1):151-159.
45. Pei B, Wang S, Guo X, et al. Arsenite-induced germline apoptosis through a MAPK-dependent,p53-independent pathway in Caenorhabditis elegans. Chem Res Toxicol.2008; 21(8):1530-1535.
46. Li JP, Yang JL. Cyclin B1 proteolysis via p38 MAPK signaling participatesin G2 checkpoint elicited by arsenite. J Cell Physiol.2007; 212(2):481-488.
47. Thorsen M, Di Y, Tangemo C, et al. The MAPK Hog1p modulates Fpslp-dependent arsenite uptake and tolerance in yeast. Mol Biol Cell. 2006;17(10):4400-4410.
48. Lau AT, Li M, Xie R, et al. Opposed arsenite-induced signaling pathways promote cell proliferation or apoptosis in cultured lung cells. Carcinogenesis. 2004;25(1):21-28.
49. Dong Z. The molecular mechanisms of arsenic-induced cell transformation and apoptosis. Environ Health Perspect.2002; 5:757-759.
50. Huang C, Ma WY, Li J, et al. Requirement of Erk, but not JNK, for arsenite-induced cell apoptosis. Environ Health Perspect.2002; 5:757-759.
51. He XQ, Chen R, Yang P, et al. Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK 1/2 in human embryo lung fibroblast cells. Toxicol Appl Pharmacol.2007; 220(1): 18-24.
52. Sakon S, Xue X, Takekawa M,et al. NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. Embo J.2003; 22(15):3898-3909.
53. Karin M. NF-kappaB and cancer:mechanisms and targets. Mol Carcinog. 2006; 45(6):355-361.
54. Bode AM, Dong Z.The paradox of arsenic:molecular mechanisms of cell transformation and chemotherapeutic effects. Crit Rev Oncol Hematol, 2002;42(1):5-24.
55. Jomova K, Jenisova Z, Feszterova M, et al. Arsenic:toxicity, oxidative stress and human disease. J.Appl.Toxicol.2011;31:95-107.
56. Leonidas C. Platanias. Biological Responses to Arsenic Compounds. J Bio Chem.2009,284(28):18583-18587.
57. Eblin KE, Bredfeldt TG, Buffington S,et al. Mitogenic signal transduction caused by monomethylarsonous acid in human bladder cells:role in arsenic-induced carcinogenesis. Toxicol Sci.2007; 95(2):321-330.
58. Altman JK, Yoon P, Katsoulidis E,et al. Regulatory effects of mammalian target of rapamycin-mediated signals in the generation of arsenic trioxide responses. J Biol Chem.2008; 283(4):1992-2001.
59. Ouyang W, Luo W, Zhang D, et al. PI93K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation. Environ Health Perspect.2008; 116(1):1-6.
60. Hamadeh HK, Vargas M, Lee E, et al. Arsenic disrupts cellular levels of p53 and mdm2:a potential mechanism of carcinogenesis. Biochem Biophys Res Commun.1999; 263(2):446-449.
61. Stommel JM, Wahl GM. Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. Embo J.2004; 23(7):1547-1556.
62. Huang Y, Zhang J, McHenry KT,et al.Induction of cytoplasmic accumulation of p53:a mechanism for low levels of arsenic exposure to predispose cells for malignant transformation.Cancer Res.2008; 68(22):9131-9136.
63. Cheng HY, Li P, David M, et al. Arsenic inhibition of the JAK-STAT pathway. Oncogene.2004; 23(20):3603-3612.
64. Stern DF, Roberts AB, Roche NS,et al. Differential responsiveness of myc-and ras-transfected cells to growth factors:selective stimulation of myc-transfected cells by epidermal growth factor. Mol Cell Biol.1986;6(3):870-877.
65. Kelekar A, Cole MD.Immortalization by c-myc, H-ras, and Ela oncogenes induces differential cellular gene expression and growth factor responses.Mol Cell Biol.1987;7(11):3899-3907.
66. Ruiz-Ramos R, Lopez-Carrillo L, Rios-Perez AD,et al. Sodium arsenite induces ROS generation, DNA oxidative damage, HO-1 and c-Myc proteins, NF-kappaB activation and cell proliferation in human breast cancer MCF-7 cells. Mutat Res.2009;674(1-2):109-115.
67. Liu J, Xie Y, Ducharme DM, et al. Global gene expression associated with hepatocarcinogenesis in adult male mice induced by in utero arsenic exposure. Environ Health Perspect.2006; 114(3):404-411.
68. Maehama T, Taylor GE,Dixon JE. PTEN an dmyotubularin:novel phosphoinositide phosphatases. Annu Rev Bioehem.2001,70:247-279.
69. Seheid MP,Woodgett JR. Phosphatidylinositol 3'Kinase signaling in mammary Tumorigenesis.J Mammary Gland Biol Neoplasia.2001; 6(1): 83-99.
70. He L,Fan C,Gillis A,et al. Coexistence of high levels of the PTEN protein with enhanced Akt activation in renal cell careinoma. Biochim Biophys Acta.2007;1772(10):1134-1142.
71. Hu Y,Li Z,Guo L, et al. MAGI-2 inhibits cell migration and proliferation via PTEN in human hepatocarcinoma cells. Arch Biochem BioPhys.2007; 467(1):1-9.
72. Lee SR, Yang KS,Kwon J, et al. Reversible in activation of the tumor suppressor PTEN by H2O2. J Biolchem.2002,277(23):20336-20342.
73. Zhang X, Jia S, Yang S, et al. Arsenic trioxide induces G2/M arrest in hepatocellular carcinoma cells by increasing the tumor suppressor PTEN expression. J Cell Biochem.2012;113(11):3528-3535.
74. Redondo MJ, Escobar DE, Hernandez DC, et al. Induction of B-chronic lymphocytic leukemia cell apoptosis by arsenic trioxide involves suppression of the phosphoinositide 3-kinase/Akt survival pathway via c-jun-NH2 terminal kinase activation and PTEN upregulation. Clin Cancer Res. 2010;16(17):4382-4391.
75. Tsou TC, Tsai FY, Yeh SC,et al. ATM/ATR-related checkpoint signals mediate arsenite-induced G2/M arrest in primary aortic endothelial cells. Arch Toxicol.2006;80(12):804-810.
76. Otto C, Giefing M, Massow A, et al. Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma. Br J Haematol. 2012;157(6):702-708.
77. Steidl C, Telenius A, Shah SP, et al. Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood.2010; 116(3):418-427.
78.杨华秀,曾永秋,曹洋,等,抑制STAT5A基因的表达对人肝癌HepG2细胞增殖的影响及其机制研究.泸州医学院学报.2012；(6)：559-563.
79. Peck AR, Witkiewicz AK, Liu C, et al. Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes. Breast Cancer Res.2012;14(5):R130.
80. Sonoki T, Harder L, Horsman DE, et al. Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies. Blood.2001; 98(9): 2837-2844.
81. Kasugai Y, Tagawa H, Kameoka Y,et al. Identification of CCND3 and BYSL as candidate targets for the 6p21 amplification in diffuse large B-cell lymphoma. Clinical Cancer Research.2005;11(23):8265-8272.
82. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature.2011; 476(7360): 298-303.
83. Schmitz R, Young RM, Ceribelli M, et al. Burkitt lymphoma pathogenesis and therapeutic targetsfrom structural and functional genomics. Nature. 2012;490(7418):116-120.
84. Sari I, Berberoglu B, Ozkara E, et al. Role of Rho-Kinase Gene Polymorphisms and Protein Expressions in Colorectal Cancer Development. Pathobiology.2013;80(3):138-145.
85. Vigil D, Kim TY, Plachco A,et al. ROCK1 and ROCK2 are required for non-small cell lung cancer anchorage-independent growth and invasion.Cancer Res.2012;72(20):5338-5347.
86. Montalvo J, Spencer C, Hackathorn A,et al. Rock1 & 2 perform overlapping and unique roles in angiogenesis and angiosarcoma tumor progression.Curr Mol Med.2013;13(1):205-219.
87. Gardian K, Janczewska S, Durlik M. Microenvironment elements involved in the development of pancreatic cancer tumor.Gastroenterol Res Pract.2012; 585674.doi:10.1155.
88. Damery S, Nichols L, Holder R,et al.Assessing the value of matrix metalloproteinase 9 (MMP9) in improving the appropriateness of referrals for colorectal cancer.Br J Cancer.2013; doi:10.1038/bjc.
1. Higginson J, DeVita VT Jr.IARC monographs on the evaluation of carcinogenic risk of chemicals to humans. Am Ind Hyg Assoc J.1980;41(5):A26, A28, A30 passim.
2. McLellan F. Arsenic contamination affects millions in Bangladesh. Lancet. 2002; 359(9312):1127.
3. Alam MG, Snow ET, Tanaka A. Arsenic and heavy metal contamination of vegetables grown in Samta village, Bangladesh. Sci Total Environ.2003; 308(1-3):83-96.
4. Matschullat J. Arsenic in the geosphere-a review. Sci Total Environ. 2000;249(1-3):297-312.
5. Sheehy JW, Jones JH. Assessment of arsenic exposures and controls in gallium arsenide production. Am Ind Hyg Assoc J.1993;54:61-69.
6. Soucy NV, Ihnat MA, Kamat CD,et al. Arsenic stimulates angiogenesis and tumorigenesis in vivo. Toxicol Sci.2003; 76(2):271-279.
7. Sun G, Li X,Pi J, et al. Current research problems of chronic arsenieosis in China. J Heaith Popul Nutr.2006; 24(2):176-181.
8.杨克敌主编.微量元素与健康.北京：科学出版社(医学出版分社).2002：295-300.
9.朗胜喜.砷及其化合物的职业危害.中国城乡企业卫生.2005；109(5)：24-25.
10. Alonso FT, Garmendia ML, Bogado ME. Increased skin cancer mortality in Chile beyond the effect of ageing:Temporal analysis 1990 to 2005. Acta Derm Venereol.2010;90(2):141-146.
11. Celik I, Gallicchio L, Boyd K, Lam TK, Matanoski G, Tao X, et al. Arsenic in drinking water and lung cancer:a systematic review. Environ Res. 2008;108(1):48-55.
12. Chen CL, Chiou HY, Hsu LI, Hsueh YM, Wu MM, Wang YH, et al. Arsenic in drinking water and risk of urinary tract cancer:a follow-up study from northeastern Taiwan. Cancer Epidemiol Biomarkers Prev.2010;19(1):101-110.
13. Meliker JR, Slotnick MJ, AvRuskin GA, Schottenfeld D, Jacquez GM, Wilson ML, et al. Lifetime exposure to arsenic in drinking water and bladder cancer:a population-based case-control study in Michigan, USA. Cancer Causes Control.2010;21(5):745-757.
14. Morales KH, Ryan L, Kuo TL, Wu MM, Chen CJ. Risk of internal cancers from arsenic in drinking water. Environ Health Perspect.2000;108(7):655-661.
15. Smith AH, Hopenhayn-Rich C, Bates MN, Goeden HM, Hertz-Picciotto I, Duggan HM, et al. Cancer risks from arsenic in drinking water. Environ Health Perspect.1992;97:259-267.
16. IARC. International Agency for Research on Cancer Special Report:Policy, Vol.10, A review of human carcinogens-Part C:Metals, arsenic, dusts, and fibres, Lancet Oncol.2009; 10,453-455.
17. Chen CJ, Wang SL, Chiou JM, et al, Arsenic and diabetes and hypertension in human populations:a review. Toxicol Appl Pharmacol.2007;222(3):298-304.
18. Tseng GH, Tai TY, Chong CK, et al. Long-term arsenic exposure and incidence of noninsulin dependent diabetes mellitus:A cohort study in arsenicosis hyperendemic villages in Taiwan. Environ Health Perspect. 2000; 108:847-851.
19. Tokar EJ, Benbrahin-Tallaa L, Ward JM, et al. Cancer in experimental animals exposed to arsenic and arsenic compounds. Critical Rev Toxicol. 2010;40:912-927.
20. Waalkes MP, Liu J, Diwan,BA. Transplacental arsenic carcinogenesis in mice. Toxicol Appl Pharmacol.2007; 222:271-280.
21. Carter DE, Aposhian HV, Gandolfi AJ. The metabolism of inorganic arsenic oxides, gallium arsenide, and arsine:A toxicochemical review. Toxicol Appl Pharmacol.2003;193:309-334.
22. Tokar EJ, Diwan BA, Waalkes MP. Arsenic exposure in utero and non-epidermal proliferative response in Tg.AC mice. Int J Toxicol. 2010;118:108-115.
23. Waalkes MP, Liu J, Ward JM, et al. Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen. Toxicol Appl Pharmacol.2006; 215:295-305.
24. Waalkes MP, Liu J, Ward JM, et al. Urogenital carcinogenesis in female CD1 mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment. Cancer Res.2006;66:1337-1345.
25. Waalkes MP, Ward JM, Diwan BA. Induction of tumors of the liver, lung, ovary and adrenal in adult mice after brief maternal gestational exposure to inorganic arsenic:promotional effects of postnatal phorbol ester exposure on hepatic and pulmonary, but not dermal cancers. Carcinogenesis.2004; 25:133-141.
26. Waalkes MP, Ward JM, Liu J, et al. Transplacental carcinogenicity of inorganic arsenic in the drinking water:induction of hepatic, ovarian, pulmonary and adrenal tumors in mice. Toxicol Appl Pharmacol.2003; 186:7-17.
27. Anderson LM. Predictive values of traditional animal bioassay studies for human perinatal carcinogenesis risk determination. Toxicol Appl Pharmacol. 2004;199:162-174.
28. Anderson LM, Diwan BA, Fear NT, et al. Critical windows of exposure for children's health:cancer in human epidemiological studies and neoplasms in experimental animal models. Environ. Health Perspect.2000;108:573-594.
29. Birnbaum, LS, Fenton SE. Cancer and developmental exposure to endocrine disruptors. Environ Health Perspect.2003; 111:389-394.
30. Polyak K, Hahn WC. Roots and stems:stem cells in cancer. Nat.Med.2005; 11:296-300.
31. Singh SK, Clarke ID, Hide T, et al. Cancer stem cells in nervous system tumors. Oncogene.2004; 23(43):7267-7273.
32. Singh SK, Clarke ID, Terasaki M, et al. Identification of acancer stem cell in human brain tumors. Cancer Res.2003; 63(18):5821-5828.
33. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature.2004; 432(7015):396-401.
34. Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA.2003; 100(25):15178-15183.
35. Richardson D, Robson CN, Lang SH, et al. CD 133, a novel marker for human prostatic epithelial stem cells. J Cell Sci.2004; 117 (Pt 16):3539-3545.
36. Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res.2005; 65(23): 10946-10951.
37. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA.2003; 100(7):3983-3988.
38. Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65(13):5506-5511.
39. Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell.2005; 8(4):323-335.
40. Perez-Losada J, Balmain A. Stem-cell hierarchy in skin cancer. Nat Rev Cancer.2003; 3(6):434-443.
41. Seigel GM, Campbell LM, Narayan M, et al. Cancer stem cell characteristics in retinoblastoma. Mol Vis.2005; 11:729-737.
42. Li C, Heidt DQ Mollenberg N, et al. Identification of pancreatic cancer stem cells. Pancreas.2005; 31(4):452.
43. Fiegel HC, Gluer S, Roth B, et al. Stem-like cells in human hepatoblastoma. J Histochem Cytochem.2004; 52(11):1495-1501.
44. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science.2004; 306(5701):1568-1571.
45. Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer.Cell.2005; 121(6):823-835.
46. Setoguchi T, Taga T, Kondo T. Cancer stem cells persist in many cancer cell lines. Cell Cycle.2004; 3(4):414-415.
47. Patrawala L, Calhoun T, Schneider-Broussard R, et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2 —cancer cells are similarly tumorigenic. Cancer Res.2005; 65(14):6207-6219.
48. Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA.2004; 101(3):781-786.
49. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer.2003; 3:895-902.
50. Polyak K, Hahn WC. Roots and stems:stem cells in cancer. Nat Med. 2005; 11:296-300.
51. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumors:accumulating evidence and unresolved questions. Nat. Rev. Cancer.2008; 8:755-768.
52. Wicha MS, Liu S, Dontu G. Cancer stem cells:An old idea a paradigm shift. Cancer Res.2006;66:1883-1890.
53. Bomken S, Fiser K, Heidenreich O, et al. Understanding the cancer stem cell. Br J Cancer.2010; 103:439-445.
54. Lobo NA, Shimono Y, Qian D, et al. The biology of cancer stem cells. Annu Rev Cell Dev Biol.2007;23:675-699.
55. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature.2001;414:105-111.
56. Kelly PN, Dakic A, Adams JM, et al. Tumor growth need not be driven by rare cancer stem cells. Science.2007; 317:337.
57. Rosen JM, Jordan CT. The increasing complexity of the cancer stem cell paradigm. Science.2009;324:1670-1673.
58. O'Brien CA, Kreso A, Jamieson CHM. Cancer stem cells and self-renewal. Clin Cancer Res.2010; 16:3113-3120.
59. Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993;9:138-141.
60. Biedermann KA, Landolph JR. Induction of anchorage independence in human diploid fore skin fibroblasts by carcinogenic metal salts. Cancer Res. 1987; 47:3815-3823.
61. Kakunaga T, Yamaski H. Transformation assay of established cell lines: mechanisms and application, Chapter 5:Neoplastic transformation in cell cultures:IN-VITRO/IN-VIVO correlations. International Agency for Research on Cancer scientific publications No.67.1985.
62. Gildea JJ, Golden WL, Harding MA, et al. Genetic and phenotypic changes associated with the acquisition of tumorigenicity in human bladder cancer. Genes Chromosomes Cancer.2000;27(3):252-263.
63. Lodish H, Berk A, Zipursky SL, et al. Molecular cell biology, Chapter 24: Cancer. WH Freeman and Company.1999; fourth edition.
64. Hart I, Hogg N. Cell adhesion and cancer, Chapter 8:Adherens junction proteins in tumor progression, Cold Spring Harbor Laboratory Press.1995.
65. Starr C, Taggart R. Biology:The Unity and Diversity of Life,5/e, Chapter 17:Control of gene expression. Wadsworth Publishing Company.1998.
66. Shilkaitis A, Green A, Steele V, et al. Neoplastic transformation of mammary epithelial cells in rats is associated with decreased apopt otic cell death, Carcinogenesis.2000; 21:227-233.
67. Zhao CQ, Young MR, Diwan BA, et al. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci USA.1997; 94(20):10907-10912.
68. Romach EH, Zhao CQ, Del Razo LM, et al. Studies on the mechanisms of arsenic-induced self tolerance developed in liver epithelial cells through continuous low-level arsenite exposure. Toxicol Sci.2000;54(2):500-508.
69. Sens DA, Park S, Gurel V, et al. Inorganic cadmium- and arsenite-induced malignant transformation of human bladder urothelial cells. Toxicol Sci.2004; 79(1):56-63.
70.胡宇,金喜梅,王国荃,等.砷诱导NIH3T3细胞转化模型的建立.新疆医科大学学报.2004；27(1)：1-5.
71. Wen G, Calaf GM, Partridge MA, et al. Neoplastic transformation of human small airway epithelial cells induced by arsenic. Mol Med.2008; 14(1-2):2-10.
72. Li Y, Ling M, Xu Y, et al. The Repressive Effect of NF-kB on p53 by Mot-2 Is Involved in Human Keratinocyte Transformation Induced by Low Levels of Arsenite. Toxicol sci.2010; 116(1):174-182.
73. Ouyang W, Luo W, Zhang D, et al. PI-3K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation. Environ Health Perspect.2008; 116(1):1-6.
74.孔贵范,曲龙.砷的分子作用机制研究现状与展望.中国地方病学杂志.2003;22：13-16.
75. Menendez D, Mora G, Salazar AM,et al. ATM status confers sensitivity to arsenic cytotoxic effects. Mutagenesis.2001; 16:443-844.
76. Yoda A, Toyoshima K, Watanabe Y, et al. Arsenic Trioxide Augments Chk2/p53-mediated Apoptosis by Inhibiting Oncogenic Wip1 Phosphatase. J Biol Chem.2008; 283(27):18969-18979.
77.Takahashi M, Ota A, Karnan S, et al. Arsenic trioxide prevents nitric oxide production in lipopolysaccharide -stimulated RAW 264.7 by inhibiting a TRIF-dependent pathway. Cancer Sci.2012;doi:10.1111/cas.12053.
78. Xia J, Li YJ, Yang QL, et al. Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer. Int. J. Mol. Sci.2012; 13:9627-9641.
79. Lau A, Whitman SA, Jaramillo MC, et al. Arsenic-Mediated Activation of the Nrf2-Keapl Antioxidant Pathway. J Biochem Mol Toxicol.2012; 27, doi: 10.1002/jbt.21463.
80. Zhang Z, Wang X, Cheng S, et al. Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/(3-catenin pathway in human colorectal adenocarcinoma DLD1 cells. Toxicol Appl Pharmacol.2011; 256(2):114-121.
81. Hayashi T, Hideshima T, Akiyama M, et al. Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow micro-environment. Mol Cancer Ther.2002; 1:851-860.
82. Qu W, Bortner CD, Sakurai T,et al. Acquisition of apoptotic resistance in arsenic-induced malignant transformation:role of the JNK signal transduction pathway. Carcinogenesis.2002;23(1):151-159.
83. Pei B, Wang S, Guo X, et al. Arsenite-induced germline apoptosis through a MAPK-dependent,p53-independent pathway in Caenorhabditis elegans. Chem Res Toxicol.2008; 21(8):1530-1535.
84. Li JP, Yang JL. Cyclin B1 proteolysis via p38 MAPK signaling participatesin G2 checkpoint elicited by arsenite. J Cell Physiol.2007; 212(2):481-488.
85. Thorsen M, Di Y, Tangemo C, et al. The MAPK Hoglp modulates Fpslp-dependent arsenite uptake and tolerance in yeast. Mol Biol Cell. 2006;17(10):4400-4410.
86. Lau AT, Li M, Xie R, et al. Opposed arsenite-induced signaling pathways promote cell proliferation or apoptosis in cultured lung cells. Carcinogenesis. 2004;25(1):21-28.
87. Dong Z. The molecular mechanisms of arsenic-induced cell transformation and apoptosis. Environ Health Perspect.2002; 5:757-759.
88. Huang C, Ma WY, Li J, et al. Requirement of Erk, but not JNK, for arsenite-induced cell apoptosis. Environ Health Perspect.2002; 5:757-759.
89. He XQ, Chen R, Yang P, et al. Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK 1/2 in human embryo lung fibroblast cells. Toxicol Appl Pharmacol.2007; 220(1): 18-24.
90. Sakon S, Xue X, Takekawa M,et al. NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. Embo J.2003; 22(15):3898-3909.
91. Karin M. NF-kappaB and cancer:mechanisms and targets. Mol Carcinog. 2006; 45(6):355-361.
92. Bode AM, Dong Z.The paradox of arsenic:molecular mechanisms of cell transformation and chemotherapeutic effects. Crit Rev Oncol Hematol, 2002;42(1):5-24.
93. Jomova K, Jenisova Z, Feszterova M, et al. Arsenic:toxicity, oxidative stress and human disease. J.Appl.Toxicol.2011;31:95-107.
94. Leonidas C. Platanias. Biological Responses to Arsenic Compounds. J Bio Chem.2009,284(28):18583-18587.
95.邓芙蓉,李艳宏,张华明,等.NaAsO2和氧苯胂对人皮肤成纤维细胞缝隙连接通讯的动态影响及作用特征.中国药理学与毒理学杂志,2002；16(5)：378-381.
96. Deng FR, Jin Y, Wang H, et al. Phenylarsine oxide inhibits gap junctional intercellular communication between human skin fibroblast cells and damages cellular DNA. J Hyg Res.2002; 31(3):151-153.
97. Fry RC, Navasumrit P, Valiathan C, et al. Activation of inflammation/NF-κB signaling in infants born to arsenic-exposed mothers. PLoS Genet.2007,3:e207.
98. Maria A, Muhammad G. Kibriya, et al. Gene Expression Profiles in Peripheral Lymphocytes by Arsenic Exposure and Skin Lesion Status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006;15:1367-1375.
99. Dower SK, Qwarnstrom EE, Page RC, et al. Biology of the interleukin-1 receptor. J Invest Dermatol.1990;94:68-73S.
100. Labow M, Shuster D, Zetterstrom M, et al. Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice.J Immunol. 1997;159:2452-2461.
101. Takami Y, Motoki T, Yamamoto I, et al. Synergistic induction of hepatocyte growth factor in human skin fibroblasts by the inflammatory cytokines interleukin-1 and interferong. Biochem Biophys Res Commun. 2005;327:212-217.
102. Liu Q, Zhang H, Smeester L, et al. The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med. Genomics.2010; 3:37.
103. Mo J, Xia Y, Wade TJ. Altered Gene Expression by Low-Dose Arsenic Exposure in Humans and Cultured Cardiomyocytes:Assessment by Real-Time PCR Arrays. Int J Environ Res Public Health.2011; 8:2090-2108.
104. Shi H, Shi X, Liu KJ. Oxidative mechanism of arsenic toxicity and carcinogenesis. Mol Cell Biochem.2004;255:67-78.
105. Cohen SM, Arnold LL, et al. Methylated arsenicals:the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Crit Rev Toxicol.2006; 36:99-133.
106. Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress.Curr Med Chem.2005;12:1161-1208.
107. Flora SJS, Bhadauria S, Kannan GM,et al. Arsenic induced oxidative stress and the role of antioxidant supplementation during chelation:a review. J Environ Biol.2007;28:333-347.
108. Applegate LA, Luscher P, Tyrrell RM. Induction of heme oxygenase:a general response to oxidant stress in cultured mammalian cell. Cancer Res.1991;51:974-978.
109. Hei Tk, Liu SX, Waldren C. Mutagenicity of arsenic in mammalian cells: Role of reactive oxygen species. Proc Natl Acad Sci USA.1998;95:8103-8107.
110. Liu SX, Athar M, Lippai I,et al. Induction of oxyradicals by arsenic: Implication for mechanism of genotoxicity. Proc Natl Acad Sei USA. 2001;98:1643-1648.
111. Ahmad S, Kichin KT, Cullen WR. Arsenic species that cause release of iron from ferritin and generation of activated oxygen. Areh Biochem BioPhys.2000;382:195-202.
112.刘力.DNA氧化损伤的修复及其与致癌的关系.中华劳动卫生职业病杂志,1999,17：181-183.
113. Matsui M, Nishigori C, Toyokuni S, et al. The role of oxidative DNA damage in human arsenic carcinogenesis:detection of 8-hydnxy-2-deoxyguanosine in arsenic-related Bowen's disease. The Journal of Investigative Dermatology,1999; 113:26-31.
114. Wanibuchi H, Hori T, Meenakshi V,et al. Promotion of rat hepatocarcinogenesis by dimethylarsinic acid:association with elevated ornithine decarboxylase activity and formation of 8-hydroxydeoxyguanosine in the liver. JPn J Caneer Res.1997;88:1149-1154.
115. Vijayaraghavan M, Wanibuchi H, Karim R, et al. Dimethylarsinic acid induces 8-hydroxy-2'-deoxyguanosine formation in the kidney of NCI-Black-Reiter rats. Cancer Lett.2001;165(1):11-17.
116.李达圣.应用单细胞凝胶电泳比较研究砷对人类DNA的损伤.中国地方病学杂志.2001；20：212-216.
117. Yamanaka K, Hasegawa A, Sawamura R,et al. Cellular response to oxidative damage in lung induced by the administration of dimethylarsinic acid, a major metabolite of inorganic arsenics, in mice. Toxicol Appl Pharmacol. 1991;108(2):205-213.
118. Brown JL, Kitchin KT. Arsenite,but not cadmium,induces ornithine decarboxylase and heme oxygenase in rat liver:relevance to arsenic careinogenesis. Caneer Lett.1996;98:227-331.
119. Germolec DR, Spalding J, Booman GA. Arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors. Mutat Res.1997;386(3):209-218.
120. Kitchin KT, Recent advance in arsenic carcinogenesis:modes of action, animal model system, and methylated arsenic metabolites. Toxic and Appl Pharmacol.2001; 172:249-261.
121.顾军,毕新岭.砷剂与角质形成细胞及其致癌机制的研究进展.国外医学皮肤性病学分册.2001；27(3)：150-152.
122. Abemathy CO, Liu YP, Longfellow D, et al. Arsenic:Health effects, mechanisms of actions, and research issues. Environ Health Perspect.1999;107:593-600.
123. Hamadeh HK, Vargas M, Lee E, et al. Arsenic disrupts cellular levels of P53 and mdm2:A potential mechanism of carcinogenesis. Biochem Biophys Res Commun.1999;263:446-449.
124. Salazar AM. Induction of p53 protein expression by sodium arsenite. Mutat Res.1997;381:259-265.
125. Mass MJ, Wang L. Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene P53 in human lung cells:A model for a mechanism of a carcinogenesis. Mutat Res.1997;263:446-449.
126. Patterson TJ, Reznikova TV, Phillips MA, et al. Arsenite maintains germinative state in cultured human epidermal cells. Toxicol Appl Pharmacol. 2005;207:69-77.
127. Patterson TJ, Rice RH. Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. Toxicol Appl Pharmacol.2007; 221:119-128.
128. Waalkes MP, Liu J, Germolec DR, et al. Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics. Cancer Res.2008; 68,8278-8285.
129. Tokar EJ, Qu W, Liu J, et al. Arsenic-specific stem cell selection during malignant transformation. J Natl Cancer Inst.2010; 102,638-649.
130. Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature.2006;442:818-822.
131. Dubrovska A, Kim S, Salamone RJ, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA.2009;106(1):268-273.
132. Groszer M, Erickson R, Scripture-Adams DD, et al. PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. Proc Natl Acad Sci USA.2006; 103(1):111-116.
133. Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukemia-initiating cells. Nature.2006; 441:475-482.
134. Sell S. Cancer stem cells and differentiation therapy. Tumor Biol.2006; 27:59-70.
135. Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature.2004;432:324-331.
136.Tokar EJ, Diwan BA, Waalkes MP. Arsenic exposure transforms human epithelial stem/progenitor cells into a cancer stem-like phenotype. Environ Health Perspect.2010;118(1):108-115.
137. Liaw J, Marshall G, Yuan Y, et al. Increased childhood liver cancer mortality and arsenic in drinking water in Northern Chile. Cancer Epidemiol Biomarkers Prev.2008;17:1982-1987.
138. Marshall G, Ferreccio C, Yuan Y, et al. Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water. J Natl Cancer Inst. 2007; 99:920-928.
139. Smith AH, Marshall G, Yuan Y, et al. Increased mortality from lung cancer and bronchiectasis in young adults after exposure to arsenic in utero and early childhood. Environ Health Perspect.2006; 114:1293-1296.
140. Yuan Y, Marshall G, Ferreccio C, et al. Kidney cancer mortality:fifty-year latency patterns related to arsenic exposure. Epidemiology.2010;21:103-108.
141. Yorifuji T, Tsuda T, Grandjean P. Unusual cancer excess after neonatal arsenic exposure from contaminated milk powder. J Natl Cancer Inst. 2010;102:360-361.
142. Aposhian HV, Zakharyan RA, Avram MD, et al. A review of the enzymology of arsenic metabolism and a new potential role of hydrogen peroxide in the detoxication of the trivalent arsenic species. Toxicol Appl Pharmacol.2004;198(3):327-335.
143. Suzuki KT, Mandal BK, Ogra Y.Speciation of arsenic in body fluids.Talanta.2002;58(1):111-119.
144. Naranmandura H, Suzuki N, Iwata K, et al. Arsenic metabolism and thioarsenicals in hamsters and rats. Chem Res Toxicol.2007;20(4):616-624.
145. Wanibuchi H, Salim EI, Kinoshita A,et al.Understanding arsenic carcinogenicity by the use of animal models.Toxicol Appl Pharmacol. 2004;198(3):366-376.
146. Soltysova A, Altanerova V, Altaner C. Cancer stem cells. Neoplasma. 2005;52(6):435-440.
147. S Huang, S Guo, F Guo, et al. CD44v6 expression in human skin keratinocytes as a possible mechanism for carcinogenesis associated with chronic arsenic exposure. European Journal of Histochemistry.2012; 57:el.
2. McLellan F. Arsenic contamination affects millions in Bangladesh. Lancet. 2002; 359(9312):1127.
3. Alam MG, Snow ET, Tanaka A. Arsenic and heavy metal contamination of vegetables grown in Samta village, Bangladesh. Sci Total Environ.2003; 308(1-3):83-96.
4. Matschullat J. Arsenic in the geosphere-a review. Sci Total Environ. 2000;249(1-3):297-312.
5. Sheehy JW, Jones JH. Assessment of arsenic exposures and controls in gallium arsenide production. Am Ind Hyg Assoc J.1993;54:61-69.
6. Soucy NV, Ihnat MA, Kamat CD,et al. Arsenic stimulates angiogenesis and tumorigenesis in vivo. Toxicol Sci.2003; 76(2):271-279.
7. Sun G, Li X,Pi J, et al. Current research problems of chronic arsenieosis in China. J Heaith Popul Nutr.2006; 24(2):176-181.
8. Alonso FT, Garmendia ML, Bogado ME. Increased skin cancer mortality in Chile beyond the effect of ageing:Temporal analysis 1990 to 2005. Acta Derm Venereol.2010;90(2):141-146.
9. Celik I, Gallicchio L, Boyd K, Lam TK, Matanoski G, Tao X, et al. Arsenic in drinking water and lung cancer:a systematic review. Environ Res. 2008;108(1):48-55.
10. Chen CL, Chiou HY, Hsu LI, Hsueh YM, Wu MM, Wang YH, et al. Arsenic in drinking water and risk of urinary tract cancer:a follow-up study from northeastern Taiwan. Cancer Epidemiol Biomarkers Prev.2010; 19(1):101-110.
11. Meliker JR, Slotnick MJ, AvRuskin GA, Schottenfeld D, Jacquez GM, Wilson ML, et al. Lifetime exposure to arsenic in drinking water and bladder cancer:a population-based case-control study in Michigan, USA. Cancer Causes Control.2010;21(5):745-757.
12. Morales KH, Ryan L, Kuo TL, Wu MM, Chen CJ. Risk of internal cancers from arsenic in drinking water. Environ Health Perspect.2000;108(7):655-661.
13. Smith AH, Hopenhayn-Rich C, Bates MN, Goeden HM, Hertz-Picciotto I, Duggan HM, et al. Cancer risks from arsenic in drinking water. Environ Health Perspect.1992;97:259-267.
14. IARC. "Some drinking-water disinfectants and contaminants, including arsenci, Monographs on chloramine, chloral and chloral hydrate, dichloroacetic acid and 3-chloro-4-(dichloromethly)- 5-hydoroxy-2(5H)-furanone". International Agency for Research on Cancer (IARC) Monographs on the Evaluation of Carcinogenic Risks to Humans.2004:269-477.
15. Chen CJ, Wang SL, Chiou JM, et al, Arsenic and diabetes and hypertension in human populations:a review. Toxicol Appl Pharmacol.2007;222(3):298-304.
16. Tseng GH, Tai TY, Chong CK, et al. Long-term arsenic exposure and incidence of noninsulin dependent diabetes mellitus:A cohort study in arsenicosis hyperendemic villages in Taiwan. Environ Health Perspect. 2000; 108:847-851.
17. Tondel M, Rahmen M,Magnuson A, et al. The relationship of arsenic levels in drinking water and the prevalence rate of skin lesions in Bangladesh.Environ Health Perspect.1999; 107:727-729.
18. Smith AH, Hopenhayn-Rich C, Bates MN,et al. Cancer risks from arsenic in drinking water. Environ Health Perspect.1992;97:259-267.
19. Pi J, Diwan BA, Sun Y, et al. Arsenic-induced malignant transformation of human keratinocytes:involvement of Nrf2. Free Radic Biol Med.2008; 45(5): 651-658.
20. Pei B, Wang S, Guo X, et al. Arsenite-induced germline apoptosis through a MAPK-dependent,p53-independent pathway in Caenorhabditis elegans. Chem Res Toxicol.2008;21(8):1530-1535.
21. Bernstam L, Nriagu J. Molecular aspects of arsenic stress. J Toxicol Environ Health B Crit Rev.2000; 3(4):293-322.
22. Polyak K, Hahn WC. Roots and stems:stem cells in cancer. Nat.Med.2005; 11:296-300.
23. Singh SK, Clarke ID, Hide T, et al. Cancer stem cells in nervous system tumors. Oncogene.2004; 23(43):7267-7273.
24. Singh SK, Clarke ID, Terasaki M, et al. Identification of acancer stem cell in human brain tumors. Cancer Res.2003; 63(18):5821-5828.
25. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature.2004; 432(7015):396-401.
26. Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA.2003; 100(25):15178-15183.
27. Richardson D, Robson CN, Lang SH, et al. CD 133, a novel marker for human prostatic epithelial stem cells. J Cell Sci.2004; 117 (Pt 16):3539-3545.
28. Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res.2005; 65(23): 10946-10951.
29. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA.2003; 100(7):3983-3988.
30. Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65(13):5506-5511.
31. Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell.2005; 8(4):323-335.
32. Perez-Losada J, Balmain A. Stem-cell hierarchy in skin cancer. Nat Rev Cancer.2003; 3(6):434-443.
33. Seigel GM, Campbell LM, Narayan M, et al. Cancer stem cell characteristics in retinoblastoma. Mol Vis.2005; 11:729-737.
34. Li C, Heidt DG, Mollenberg N, et al. Identification of pancreatic cancer stem cells. Pancreas.2005; 31(4):452.
35. Fiegel HC, Gluer S, Roth B, et al. Stem-like cells in human hepatoblastoma. J Histochem Cytochem.2004; 52(11):1495-1501.
36. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science.2004; 306(5701):1568-1571.
37. Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer.Cell.2005; 121(6):823-835.
38. Setoguchi T, Taga T, Kondo T. Cancer stem cells persist in many cancer cell lines. Cell Cycle.2004; 3(4):414-415.
39. Patrawala L, Calhoun T, Schneider-Broussard R, et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2-cancer cells are similarly tumorigenic. Cancer Res.2005; 65(14): 6207-6219.
40. Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA.2004; 101(3):781-786.
41. Yuan Li,Min Ling,Yuan Xu, et al. The Repressive Effect of NF-kB on p53 by Mot-2 Is Involved in Human Keratinocyte Transformation Induced by Low Levels of Arsenite. Toxicol sci.2010; 116(1):174-182.
42. Ouyang W, Luo W, Zhang D, et al. PI-3K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation. Environ Health Perspect.2008; 116(1):1-6.
43. Patterson TJ, Reznikova TV, Phillips MA, et al. Arsenite maintains germinative state in cultured human epidermal cells. Toxicol Appl Pharmacol. 2005;207:69-77.
44. Patterson TJ, Rice RH. Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. Toxicol Appl Pharmacol.2007; 221:119-128.
45. Waalkes MP, Liu J, Germolec DR, et al. Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics. Cancer Res.2008; 68,8278-8285.
46. Tokar EJ, Diwan BA, Waalkes MP. Arsenic exposure transforms human stem/progenitor cells into a cancer stem cell-like phenotype. Environ Health Perspect.2010;118:108-115.
47. Tokar EJ, Qu W, Liu J, et al. Arsenic-specific stem cell selection during malignant transformation. J Natl Cancer Inst.2010; 102,638-649.
48. Reya T, Morrison SJ, Clarke MF, et al. Stem cells,cancer, and cancer stem cells.Nature.2001;414:105-111.
49. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer.2003;3:895-902.
50. Lobo NA, Shimono Y, Qian D, et al. The biology of cancer stem cells. Annu Rev Cell Dev Biol.2007; 23:675-699.
51. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumors:accumulating evidence and unresolved questions. Nat Rev Cancer.2008; 8:755-768.
52. Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature.2006;442:818-822.
1. IARC. "Some drinking-water disinfectants and contaminants, including arsenci, Monographs on chloramine, chloral and chloral hydrate, dichloroacetic acid and 3-chloro-4-(dichloromethly)- 5-hydoroxy-2(5H)-furanone". International Agency for Research on Cancer (IARC) Monographs on the Evaluation of Carcinogenic Risks to Humans.2004:269-477.
2. Alonso FT, Garmendia ML, Bogado ME. Increased skin cancer mortality in Chile beyond the effect of ageing:Temporal analysis 1990 to 2005. Acta Derm Venereol.2010;90(2):141-146.
3. Celik I, Gallicchio L, Boyd K, et al. Arsenic in drinking water and lung cancer: a systematic review. Environ Res.2008;108(1):48-55.
4. Chen CL, Chiou HY, Hsu LI, et al. Arsenic in drinking water and risk of urinary tract cancer:a follow-up study from northeastern Taiwan. Cancer Epidemiol Biomarkers Prev.2010; 19(1):101-110.
5. Meliker JR, Slotnick MJ, AvRuskin GA, et al. Lifetime exposure to arsenic in drinking water and bladder cancer:a population-based case-control study in Michigan, USA. Cancer Causes Control.2010;21(5):745-757.
6. Morales KH, Ryan L, Kuo TL,et al. Risk of internal cancers from arsenic in drinking water. Environ Health Perspect.2000;108(7):655-661.
7. Smith AH, Hopenhayn-Rich C, Bates MN, et al. Cancer risks from arsenic in drinking water. Environ Health Perspect.1992;97:259-267.
8.Pi.J, Diwan. BA, Sun Y, et al. Arsenic-induced malignant transformation of human keratinocytes:involvement of Nrf2. Free Radic Biol Med.2008;45(5): 651-658.
9. Pei B, Wang S, Guo X, et al. Arsenite-induced germline apoptosis through a MAPK-dependent,p53-independent pathway in Caenorhabditis elegans. Chem Res Toxicol.2008;21(8):1530-1535.
10. Bernstam L, Nriagu J. Molecular aspects of arsenic stress. J Toxicol Environ Health B Crit Rev.2000;3(4):293-322.
11. Marinissen MJ, Sevritja JM, Oeffmrnnas S, et al. Thrombin Portease-ativated receptor singals through Gq-and G13-initiated MAPK cascades regulating c-Jun expression to induce cell trnasofmration. J Biol Chem.2003;278(47):46814-46825.
12. Bridge JW, Benofdr DJ, Hubbdar SA. The design and use of invro toxicity tests. In:RTumer(Ed), Animals in Scientific Research:An effective substitute for man? Maemillina,London.1983:47.
13.刘国谦.细胞毒理学.北京.军事医学科学出版社.2001：287-291.
14. Ouyang W, Luo W, Zhang D, et al. PI-3K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation. Environ Health Perspect.2008; 116(1):1-6.
15. Boukamp P, Petrussevska RT, Breitkreutz D, et al. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol. 1988;106(3):761-771.
16. Pinlaor S, Ma N, Hiraku Y, et al. Repeated infection with Opisthorchis viverrini induces accumulation of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanine in the bile duct of hamsters via inducible nitric oxide synthase. Carcinogenesis.2004;25(8):1535-1542.
17. Bodwell JE, Kingsley LA, Hamilton JW. Arsenic at very low concentrations alters glucocorticoid receptor (GR)-mediated gene activation but not GR-mediated gene repression:complex dose-response effects are closely correlated with levels of activated GR and require a functional GR DNA binding domain. Chem Res Toxicol.2004; 17(8):1064-1076.
18. He XQ, Chen R, Yang P, et al. Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK1/2 in human embryo lung fibroblast cells. Toxicol Appl Pharmacol. 2007;220(1):18-24.
19. Shen S, Lee J, Weinfeld M, Le XC. Attenuation of DNA damage-induced p53 expression by arsenic:a possible mechanism for arsenic co-carcinogenesis. Mol Carcinog.2008 Jul;47(7):508-518.
20. Wen G, Calaf GM, Partridge MA, et al. Neoplastic transformation of human small airway epithelial cells induced by arsenic. Mol Med.2008;14(1-2):2-10.
21. Zhao CQ, Young MR, Diwan BA, et al. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci USA.1997; 94(20):10907-10912.
22. Romach EH, Zhao CQ, Del Razo LM, et al. Studies on the mechanisms of arsenic-induced self tolerance developed in liver epithelial cells through continuous low-level arsenite exposure. Toxicol Sci.2000;54(2):500-508.
23. Sens DA, Park S, Gurel V, et al. Inorganic cadmium- and arsenite-induced malignant transformation of human bladder urothelial cells. Toxicol Sci.2004; 79(1):56-63.
24.胡宇,金喜梅,王国荃,等.砷诱导NIH3T3细胞转化模型的建立.新疆医科大学学报.2004；27(1)：1-5.
25. Wen G, Calaf GM, Partridge MA, et al. Neoplastic transformation of human small airway epithelial cells induced by arsenic. Mol Med.2008; 14(1-2):2-10.
26. Li Y, Ling M, Xu Y, et al. The Repressive Effect of NF-kB on p53 by Mot-2 Is Involved in Human Keratinocyte Transformation Induced by Low Levels of Arsenite. Toxicol sci.2010; 116(1):174-182.
27. Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology.4th edition.New York:W. H. Freeman; 2000.
28. Gildea JJ, Golden WL, Harding MA, et al.Genetic and phenotypic changes associated with the acquisition of tumorigenicity in human bladder cancer. Genes Chromosomes Cancer.2000;27(3):252-263.
29. Funk JO, Kind P. Cell cycle control, genetic instability and cancer. Hautarzt. 1997;48(3):157-165.
30. Hakem R. DNA-damage repair; the good, the bad, and the ugly. Embo J. 2008.27(4):589-605.
31. Londhe VA, Nguyen HT, Jeng JM, et al. NF-κB induces lung maturation during mouse lung morphogenesis. Dev Dyn.2008; 237(2):328-338.
32. Halazonetis TD, Gorgoulis VG, Bartek J. An oncogene-induced DNA damage model for cancer development. Science.2008;319(5868):1352-1355.
33.金银龙,陈昌杰,陈西平,等.生活饮用水卫生标准GB5749-2006.中国标准出版社.2007.
34. US EPA. Drinking Water Standards and Health Advisories. Winter 2004.
1. International Agency for Researchon Cancer(1ARC). Monographs on the evaluation of the carcinogenic risk of chemicals to man overall evaluation of carcinogenicity:all update of IARC monographs 1 to 42:arsenic and arsenic compounds. France:IARC,1987:100-106.
2. Polyak K, Hahn WC. Roots and stems:stem cells in cancer. Nat.Med.2005; 11:296-300.
3. Singh SK, Clarke ID, Hide T, et al. Cancer stem cells in nervous system tumors. Oncogene.2004; 23(43):7267-7273.
4. Singh SK, Clarke ID, Terasaki M, et al. Identification of acancer stem cell in human brain tumors. Cancer Res.2003; 63(18):5821-5828.
5. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature.2004; 432(7015):396-401.
6. Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA.2003; 100(25):15178-15183.
7. Richardson D, Robson CN, Lang SH, et al. CD 133, a novel marker for human prostatic epithelial stem cells. J Cell Sci.2004; 117 (Pt 16):3539-3545.
8. Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res.2005; 65(23):10946-10951.
9. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA.2003; 100(7):3983-3988.
10. Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65(13):5506-5511.
11. Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell.2005; 8(4):323-335.
12. Perez-Losada J, Balmain A. Stem-cell hierarchy in skin cancer. Nat Rev Cancer.2003; 3(6):434-443.
13. Seigel GM, Campbell LM, Narayan M, et al. Cancer stem cell characteristics in retinoblastoma. Mol Vis.2005; 11:729-737.
14. Li C, Heidt DG, Mollenberg N, et al. Identification of pancreatic cancer stem cells. Pancreas.2005; 31(4):452.
15. Fiegel HC, Gluer S, Roth B, et al. Stem-like cells in human hepatoblastoma. J Histochem Cytochem.2004; 52(11):1495-1501.
16. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science.2004; 306(5701):1568-1571.
17. Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer.Cell.2005; 121(6):823-835.
18. Setoguchi T, Taga T, Kondo T. Cancer stem cells persist in many cancer cell lines. Cell Cycle.2004; 3(4):414-415.
19. Patrawala L, Calhoun T, Schneider-Broussard R, et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2 —ancer cells are similarly tumorigenic. Cancer Res.2005; 65(14):6207-6219.
20. Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA.2004; 101(3):781-786.
21. Patterson TJ, Reznikova TV, Phillips MA, et al. Arsenite maintains germinative state in cultured human epidermal cells. Toxicol Appl Pharmacol. 2005;207:69-77.
22. Patterson TJ, Rice RH. Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. Toxicol Appl Pharmacol.2007; 221:119-128.
23. Waalkes MP, Liu J, Germolec DR, et al. Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics. Cancer Res.2008; 68,8278-8285.
24. Tokar EJ, Diwan BA, Waalkes MP. Arsenic exposure transforms human stem/progenitor cells into a cancer stem cell-like phenotype. Environ Health Perspect.2010; 118:108-115.
25. Tokar EJ, Qu W, Liu J, et al. Arsenic-specific stem cell selection during malignant transformation. J Natl Cancer Inst.2010; 102,638-649.
26. Omran OM, Ata HS. CD44s and CD44v6 in diagnosis and prognosis of human bladder cancer. Ultrastruct Pathol.2012;36(3):145-152.
27. Gunthert U, Hofinann M, Rudy W, et al. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 1991;65(1):13-24.
28. Zhou ZJ, Dai Z, Zhou SL, et al. Overexpression of HnRNP A1 promotes tumor invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma. Int J Cancer.2013; 132(5):1080-1089.
29. Gun BD, Bahadir B, Bektas S, et al. Clinicopathological significance of fascin and CD44v6 expression in endometrioid carcinoma. Diagn Pathol. 2012;7(1):80.
30. Goodison S, Urquidi V, Tarin D. CD44 cell adhesion molecules. Molecular Pathology.1999; 52(4):189-196.
31. Turley EA, Noble PW, Bourguignon LY. Signaling properties of hyaluronan receptors. J Biol Chem.2002;277(7):4589-4592.
32. Welsh CF, Zhu D, Bourguignon LY. Interaction of CD44 variant isoforms with hyaluronic acid and the cytoskeleton in human prostate cancer cells. J Cell Physiol.1995;164(3):605-612.
33. Matsumura Y, Hanbury D, Smith J,et al. Non-invasive detection of malignancy by identification of unusual CD44 gene activity in exfoliated cancer cells.BMJ.1994;308(6929):619-624.
34. Peng J, Lu JJ, Zhu J, et al. Prediction of Treatment Outcome by CD44v6 After Total Mesorectal Excision in Locally Advanced Rectal Cancer. The Cancer Journal.2008;14(1):54-61.
35.张增锋,韦敏怡,李德进,等.鼻咽癌中CD44v6和nm-23H1的表达与淋巴 结转移的关系.广西医科大学学报.2001；18(4)：473.
36. Wang DR, Chen GY, Liu XL, et al. CD44v6 in peripheral blood and bone marrow of patients with gastric cancer as micro-metastasis. World J Gastroenterol.2006;12(1):36-42.
37. Saito H, Tsujiiani S, Katano K, et al. Serum concentration of CD44 variant 6 and its relation to prognosis in patients with gastric carcinoma. Cancer.1998; 83(6):1094-1101.
38. Lamb RE, Hennigan RF, Tumbull UK,et al. AP-1-mediated invasion requires increased expression of the hyaluronan receptor CD44. Mol Cell Biol.1997;17(2):963-976.
39. Colnot DR, Quak JJ, Roos JC,et al. Phase I therapy study of 186Re-labeled chimeric monoclonal antibody U36 in patients with squamous cell carcinoma of the head and neck. J Nucl Med.2000;41(12):1999-2010.
40. Heider KH, Kuthan H, Stehle G, et al. CD44v6:a target for antibody-based cancer therapy. Cancer Immunol Immunother.2004; 53(7):567-579.
41. Halazonetis TD, Gorgoulis VG, Bartek J. An oncogene-induced DNA damage model for cancer development. Science.2008;319(5868):1352-1355.
42. Protrka Z, Arsenijevic S, Dimitrijevic A, et al. Co-overexpression of bcl-2 and c-myc in uterine cervix carcinomas and premalignant lesions. Eur J Histochem.2011;55(1):e8.
43. Konstantakou EG, Voutsinas GE, Karkoulis PK. Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses. Int J Oncol.2009; 35(2):401-416.
44. Lim do Y, Park JH. Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. Am J Physiol Gastrointest Liver Physiol.2009;296(5):G1060-1068.
45. Aylon Y, Oren M. Living with p53, dying of p53. Cell.2007; 130(4):597-600.
46. Kastan MB. Wild-type p53:tumors can't stand it. Cell.2007;128(5):837-840.
47. De Chaudhuri S, Kundu M, Banerjee M,et al. Arsenic-induced health effects and genetic damage in keratotic individuals:involvement of p53 arginine variant and chromosomal aberrations in arsenic susceptibility. Mutat Res. 2008;659(1-2):118-125.
48. Shen S, Lee J, Weinfeld M, et al. Attenuation of DNA damage-induced p53 expression by arsenic:a possible mechanism for arsenic co-carcinogenesis. Mol Carcinog.2008; 47(7):508-518.
49. Huang Y, Zhang J, McHenry KT,et al. Induction of cytoplasmic accumulation of p53:a mechanism for low levels of arsenic exposure to predispose cells for malignant transformation.Cancer Res.2008;68(22): 9131-9136.
50. Stommel JM, Wahl GM. Accelerated MDM2 auto-degradation induced by DNA-damage is required for p53 activation. Embo J.2004; 23(7):1547-1556.
51. Hamadeh HK, Vargas M, Lee E,et al. Arsenic disrupts cellular levels of p53 and mdm2:a potential mechanism of carcinogenesis. Biochem Biophys Res Commun.1999;263(2):446-449.
52. Tergaonkar V, Perkins ND. p53 and NF-kappaB crosstalk:IKKalpha tips the balance. Mol Cell.2007;26(2):158-159.
53. Karin M, Cao Y, Greten FR, et al.NF-kappaB in cancer:from innocent bystander to major culprit.Nat Rev Cancer.2002;2(4):301-310.
54. Sakon S, Xue X, Takekawa M, et al. NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. Embo J.2003;22(15):3898-3909.
55. Karin M. NF-kappaB and cancer:mechanisms and targets. Mol Carcinog. 2006;45(6):355-361.
56. Jeong SJ, Pise-Masison CA, Radonovich MF, et al. A novel NF-kappaB pathway involving IKKbeta and p65/RelA Ser-536 phosphorylation results in p53 Inhibition in the absence of NF-kappaB transcriptional activity. J Biol Chem. 2005; 280(11):10326-10332.
57. Campo GM, Avenoso A, Campo S, et al. NF-kB and caspases are involved in the hyaluronan and chondroitin-4-sulphate-exerted antioxidant effect in fibroblast cultures exposed to oxidative stress. J Appl Toxicol.2008; 28(4): 509-517.
58. Huang WC, Ju TK, Hung MC, et al. Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Mol Cell.2007;26(1):75-87.
59. Sherine T, Seema S, Conrad T, et al. Kindlin-2 Expression in Arsenite and Cadmium Transformed Bladder Cancer Cell Lines and in Archival Specimens of Human Bladder Cancer. Urology.2011; 77(6):1507.el-1507.e7.
60. Serkan Sertel, Margaret Tome, Margaret M. Briehl, Judith Bauer, Kai Hock, et al. Factors Determining Sensitivity and Resistance of Tumor Cells to Arsenic Trioxide. PLoS One.2012;7(5):e35584.
61. Udensi UK, Cohly HH, Graham-Evans BE, et al. Aberrantly expressed Genes in HacaT Keratinocytes chronically exposed to Arsenic Trioxide. Biomarker Insights.2011; 6:7-16.
62. Bae DS, Handa RJ, Yang RS, et al. Gene Expression Patterns as Potential Molecular Biomarkers for Malignant Transformation in Human Keratinocytes Treated with MNNG, Arsenic, or a Metal Mixture. Toxicol sci.2003;74:32-42.
63. Bae DS, Hanneman WH, Yang RS, et al. Characterization of gene expression changes associated with MNNG, arsenic, or metal mixture treatment in human keratinocytes:application of cDNA microarray technology. Environ Health Perspect.2002; 110 Suppl 6:931-941.
1. Powell CL,Kosyk O,Bradford BU,et al. Temporal correlation of Pathology and DNA damage with gene expression in a choline-deficient model of rat liver injury. Hepatology.2005;42(5):1137-1147.
2. Kremer A, Schneider R, Terstappen GC. A bioinformatics perspective on proteomics:data storage, analysis, and integration. Biosci Rep.2005; 25(1-2): 95-106.
3. Waters MD, Fostel JM. Toxicogenomics and systems toxicology:aims and prospects. Nat Rev Genet.2004; 5:936-948.
4. Argos M, Kibriya MG, Parvez F, et al. Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev.2006; 15:1367-1375.
5. States JC, Singh AV, Knudsen TB, et al. Prenatal Arsenic Exposure Alters Gene Expression in the Adult Liver to a Proinflammatory State Contributing to Accelerated Atherosclerosis. PLoS ONE.2012; 7(6):e38713.
6. Liu J, Xie Y, Ducharme DM, et al. Global gene expression associated with hepatocarcinogenesis in adult male mice induced by in utero arsenic exposure. Environ Health Perspect.2006; 114:404-411.
7. Sasaki A, Oshima Y, Fujimura A. An approach to elucidate potential mechanism of renal toxicity of arsenic trioxide. Exp Hematol.2007; 35:252-262.
8. Posey T, Weng T, Chen Z, et al. Arsenic-induced changes in the gene expression of lung epithelial L2 cells:implications in carcinogenesis. BMC Genomics.2008; 9:115.
9. Su PF, Hu YJ, Ho IC, et al. Distinct gene expression profiles in immortalized human urothelial cells exposed to inorganic arsenite and its methylated trivalent metabolites. Environ Health Perspect.2006; 114:394-403.
10. Wang XJ, Yang J, Cang H,et al. Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Research.2005; 15(7):511-522.
11. Komissarova EV, Li P, Uddin AN et al. Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite:Identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol.2008; 226(2):199-205.
12. Sertel S, Tome M, Briehl MM, et al. Factors Determining Sensitivity and Resistance of Tumor Cells to Arsenic Trioxide. PLoS One.2012;7(5):e35584.
13. George Casella, Roger L. Berger. Statistic inference. Chapter2. Proc Natl Acad Sci USA.
14. Tusher VG, Tibshirani R, Chu G.Significance analysis of microarrays applied to the ionizing radiation response.2001;98(9):5116-5121.
15. Cox TF, Cox MAA. Multidimensional scaling. Chapman and Hall.1994.
16. JL Rodgers, WA Nicewander. Thirteen ways to look at the correlation coefficient. The American Statistician.1988; 42(1):59-66.
17. Stephen M. Stigler. Francis Galton's Account of the Invention of Correlation. Statist. Sci.1989;4(2):73-79.
18. Anderberg,Michael R. Cluster Analysis for Applications. academic press. 1973;New York.
19. Oliver Dreesen, Ali H. Bri vanlou. Signaling Pathways in Cancer and Embryonic Stem Cells. Stem Cell Rev.2007;3(1):7-17.
20. DurrR,CaselmannWH.Carcinogenesis of Primary liver malignaneies. Langenbecks Aieh Surg.2000;385(3):154-161.
21. Bodwell JE, Kingsley LA, Hamilton JW. Arsenic at very low concentrations alters glucocorticoid receptor (GR)-mediated gene activation but not GR-mediated gene repression:complex dose-response effects are closely correlated with levels of activated GR and require a functional GR DNA binding domain. Chem Res Toxicol.2004; 17(8):1064-1076.
22.He XQ, Chen R, Yang P,et al. Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK1/2 in human embryo lung fibroblast cells. Toxicol Appl Pharmacol.2007;220(1):18-24.
23. Shen S, Lee J, Weinfeld M, et al. Attenuation of DNA damage-induced p53 expression by arsenic:a possible mechanism for arsenic co-carcinogenesis. Mol Carcinog.2008;47(7):508-518.
24. Wen G, Calaf GM, Partridge MA, et al. Neoplastic transformation of human small airway epithelial cells induced by arsenic. Mol Med.2008;14(1-2):2-10.
25. NRC. Arsenic in the drinking water. National Research Council, National Academy; Washington, DC.2001:1-244.
26.孔贵范,曲龙.砷的分子作用机制研究现状与展望.中国地方病学杂志.2003；22：13-16.
27. Douglas Hanahan, Robert A. Weinberg. Hallmarks of Cancer:The Next Generation. Cell.2011;144(5):646-674.
28. Bozzuto G, Ruggieri P, Molinari A. Molecular aspects of tumor cell migration and invasion. Ann Ist Super Sanita.2010; 46(1):66-80.
29. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta.2013;1830(2):2481-2495.
30. Fry RC, Navasumrit P, Valiathan C, et al. Activation of inflammation/NF-KB signaling in infants born to arsenic-exposed mothers. PLoS Genet.2007,3:e207.
31. Maria A, Muhammad G. Kibriya, et al. Gene Expression Profiles in Peripheral Lymphocytes by Arsenic Exposure and Skin Lesion Status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006;15:1367-1375.
32. Dower SK, Qwarnstrom EE, Page RC, et al. Biology of the interleukin-1 receptor. J Invest Dermatol.1990;94:68-73S.
33. Labow M, Shuster D, Zetterstrom M, et al. Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice.J Immunol. 1997;159:2452-2461.
34. Takami Y, Motoki T, Yamamoto I, et al. Synergistic induction of hepatocyte growth factor in human skin fibroblasts by the inflammatory cytokines interleukin-1 and interferong. Biochem Biophys Res Commun. 2005;327:212-217.
35. Liu Q, Zhang H, Smeester L, et al. The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med. Genomics.2010; 3:37.
36. Mo J, Xia Y, Wade TJ. Altered Gene Expression by Low-Dose Arsenic Exposure in Humans and Cultured Cardiomyocytes:Assessment by Real-Time PCR Arrays. Int J Environ Res Public Health.2011; 8:2090-2108.
37. Menendez D, Mora G, Salazar AM,et al. ATM status confers sensitivity to arsenic cytotoxic effects. Mutagenesis.2001; 16:443-844.
38. Yoda A, Toyoshima K, Watanabe Y, et al. Arsenic Trioxide Augments Chk2/p53-mediated Apoptosis by Inhibiting Oncogenic Wipl Phosphatase. J Biol Chem.2008; 283(27):18969-18979.
39.Takahashi M, Ota A, Karnan S, et al. Arsenic trioxide prevents nitric oxide production in lipopolysaccharide -stimulated RAW 264.7 by inhibiting a TRIF-dependent pathway. Cancer Sci.2012;doi:10.1111/cas.12053.
40. Xia J, Li YJ, Yang QL, et al. Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer. Int. J. Mol. Sci.2012; 13:9627-9641.
41. Lau A, Whitman SA, Jaramillo MC, et al. Arsenic-Mediated Activation of the Nrf2-Keapl Antioxidant Pathway. J Biochem Mol Toxicol.2013; 27(2): 99-105.
42. Zhang Z, Wang X, Cheng S, et al. Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/β-catenin pathway in human colorectal adenocarcinoma DLD1 cells. Toxicol Appl Pharmacol.2011; 256(2):114-121.
43. Hayashi T, Hideshima T, Akiyama M, et al. Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow micro-environment. Mol Cancer Ther.2002; 1:851-860.
44. Qu W, Bortner CD, Sakurai T,et al. Acquisition of apoptotic resistance in arsenic-induced malignant transformation:role of the JNK signal transduction pathway. Carcinogenesis.2002;23(1):151-159.
45. Pei B, Wang S, Guo X, et al. Arsenite-induced germline apoptosis through a MAPK-dependent,p53-independent pathway in Caenorhabditis elegans. Chem Res Toxicol.2008; 21(8):1530-1535.
46. Li JP, Yang JL. Cyclin B1 proteolysis via p38 MAPK signaling participatesin G2 checkpoint elicited by arsenite. J Cell Physiol.2007; 212(2):481-488.
47. Thorsen M, Di Y, Tangemo C, et al. The MAPK Hog1p modulates Fpslp-dependent arsenite uptake and tolerance in yeast. Mol Biol Cell. 2006;17(10):4400-4410.
48. Lau AT, Li M, Xie R, et al. Opposed arsenite-induced signaling pathways promote cell proliferation or apoptosis in cultured lung cells. Carcinogenesis. 2004;25(1):21-28.
49. Dong Z. The molecular mechanisms of arsenic-induced cell transformation and apoptosis. Environ Health Perspect.2002; 5:757-759.
50. Huang C, Ma WY, Li J, et al. Requirement of Erk, but not JNK, for arsenite-induced cell apoptosis. Environ Health Perspect.2002; 5:757-759.
51. He XQ, Chen R, Yang P, et al. Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK 1/2 in human embryo lung fibroblast cells. Toxicol Appl Pharmacol.2007; 220(1): 18-24.
52. Sakon S, Xue X, Takekawa M,et al. NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. Embo J.2003; 22(15):3898-3909.
53. Karin M. NF-kappaB and cancer:mechanisms and targets. Mol Carcinog. 2006; 45(6):355-361.
54. Bode AM, Dong Z.The paradox of arsenic:molecular mechanisms of cell transformation and chemotherapeutic effects. Crit Rev Oncol Hematol, 2002;42(1):5-24.
55. Jomova K, Jenisova Z, Feszterova M, et al. Arsenic:toxicity, oxidative stress and human disease. J.Appl.Toxicol.2011;31:95-107.
56. Leonidas C. Platanias. Biological Responses to Arsenic Compounds. J Bio Chem.2009,284(28):18583-18587.
57. Eblin KE, Bredfeldt TG, Buffington S,et al. Mitogenic signal transduction caused by monomethylarsonous acid in human bladder cells:role in arsenic-induced carcinogenesis. Toxicol Sci.2007; 95(2):321-330.
58. Altman JK, Yoon P, Katsoulidis E,et al. Regulatory effects of mammalian target of rapamycin-mediated signals in the generation of arsenic trioxide responses. J Biol Chem.2008; 283(4):1992-2001.
59. Ouyang W, Luo W, Zhang D, et al. PI93K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation. Environ Health Perspect.2008; 116(1):1-6.
60. Hamadeh HK, Vargas M, Lee E, et al. Arsenic disrupts cellular levels of p53 and mdm2:a potential mechanism of carcinogenesis. Biochem Biophys Res Commun.1999; 263(2):446-449.
61. Stommel JM, Wahl GM. Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. Embo J.2004; 23(7):1547-1556.
62. Huang Y, Zhang J, McHenry KT,et al.Induction of cytoplasmic accumulation of p53:a mechanism for low levels of arsenic exposure to predispose cells for malignant transformation.Cancer Res.2008; 68(22):9131-9136.
63. Cheng HY, Li P, David M, et al. Arsenic inhibition of the JAK-STAT pathway. Oncogene.2004; 23(20):3603-3612.
64. Stern DF, Roberts AB, Roche NS,et al. Differential responsiveness of myc-and ras-transfected cells to growth factors:selective stimulation of myc-transfected cells by epidermal growth factor. Mol Cell Biol.1986;6(3):870-877.
65. Kelekar A, Cole MD.Immortalization by c-myc, H-ras, and Ela oncogenes induces differential cellular gene expression and growth factor responses.Mol Cell Biol.1987;7(11):3899-3907.
66. Ruiz-Ramos R, Lopez-Carrillo L, Rios-Perez AD,et al. Sodium arsenite induces ROS generation, DNA oxidative damage, HO-1 and c-Myc proteins, NF-kappaB activation and cell proliferation in human breast cancer MCF-7 cells. Mutat Res.2009;674(1-2):109-115.
67. Liu J, Xie Y, Ducharme DM, et al. Global gene expression associated with hepatocarcinogenesis in adult male mice induced by in utero arsenic exposure. Environ Health Perspect.2006; 114(3):404-411.
68. Maehama T, Taylor GE,Dixon JE. PTEN an dmyotubularin:novel phosphoinositide phosphatases. Annu Rev Bioehem.2001,70:247-279.
69. Seheid MP,Woodgett JR. Phosphatidylinositol 3'Kinase signaling in mammary Tumorigenesis.J Mammary Gland Biol Neoplasia.2001; 6(1): 83-99.
70. He L,Fan C,Gillis A,et al. Coexistence of high levels of the PTEN protein with enhanced Akt activation in renal cell careinoma. Biochim Biophys Acta.2007;1772(10):1134-1142.
71. Hu Y,Li Z,Guo L, et al. MAGI-2 inhibits cell migration and proliferation via PTEN in human hepatocarcinoma cells. Arch Biochem BioPhys.2007; 467(1):1-9.
72. Lee SR, Yang KS,Kwon J, et al. Reversible in activation of the tumor suppressor PTEN by H2O2. J Biolchem.2002,277(23):20336-20342.
73. Zhang X, Jia S, Yang S, et al. Arsenic trioxide induces G2/M arrest in hepatocellular carcinoma cells by increasing the tumor suppressor PTEN expression. J Cell Biochem.2012;113(11):3528-3535.
74. Redondo MJ, Escobar DE, Hernandez DC, et al. Induction of B-chronic lymphocytic leukemia cell apoptosis by arsenic trioxide involves suppression of the phosphoinositide 3-kinase/Akt survival pathway via c-jun-NH2 terminal kinase activation and PTEN upregulation. Clin Cancer Res. 2010;16(17):4382-4391.
75. Tsou TC, Tsai FY, Yeh SC,et al. ATM/ATR-related checkpoint signals mediate arsenite-induced G2/M arrest in primary aortic endothelial cells. Arch Toxicol.2006;80(12):804-810.
76. Otto C, Giefing M, Massow A, et al. Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma. Br J Haematol. 2012;157(6):702-708.
77. Steidl C, Telenius A, Shah SP, et al. Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood.2010; 116(3):418-427.
78.杨华秀,曾永秋,曹洋,等,抑制STAT5A基因的表达对人肝癌HepG2细胞增殖的影响及其机制研究.泸州医学院学报.2012；(6)：559-563.
79. Peck AR, Witkiewicz AK, Liu C, et al. Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes. Breast Cancer Res.2012;14(5):R130.
80. Sonoki T, Harder L, Horsman DE, et al. Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies. Blood.2001; 98(9): 2837-2844.
81. Kasugai Y, Tagawa H, Kameoka Y,et al. Identification of CCND3 and BYSL as candidate targets for the 6p21 amplification in diffuse large B-cell lymphoma. Clinical Cancer Research.2005;11(23):8265-8272.
82. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature.2011; 476(7360): 298-303.
83. Schmitz R, Young RM, Ceribelli M, et al. Burkitt lymphoma pathogenesis and therapeutic targetsfrom structural and functional genomics. Nature. 2012;490(7418):116-120.
84. Sari I, Berberoglu B, Ozkara E, et al. Role of Rho-Kinase Gene Polymorphisms and Protein Expressions in Colorectal Cancer Development. Pathobiology.2013;80(3):138-145.
85. Vigil D, Kim TY, Plachco A,et al. ROCK1 and ROCK2 are required for non-small cell lung cancer anchorage-independent growth and invasion.Cancer Res.2012;72(20):5338-5347.
86. Montalvo J, Spencer C, Hackathorn A,et al. Rock1 & 2 perform overlapping and unique roles in angiogenesis and angiosarcoma tumor progression.Curr Mol Med.2013;13(1):205-219.
87. Gardian K, Janczewska S, Durlik M. Microenvironment elements involved in the development of pancreatic cancer tumor.Gastroenterol Res Pract.2012; 585674.doi:10.1155.
88. Damery S, Nichols L, Holder R,et al.Assessing the value of matrix metalloproteinase 9 (MMP9) in improving the appropriateness of referrals for colorectal cancer.Br J Cancer.2013; doi:10.1038/bjc.
1. Higginson J, DeVita VT Jr.IARC monographs on the evaluation of carcinogenic risk of chemicals to humans. Am Ind Hyg Assoc J.1980;41(5):A26, A28, A30 passim.
2. McLellan F. Arsenic contamination affects millions in Bangladesh. Lancet. 2002; 359(9312):1127.
3. Alam MG, Snow ET, Tanaka A. Arsenic and heavy metal contamination of vegetables grown in Samta village, Bangladesh. Sci Total Environ.2003; 308(1-3):83-96.
4. Matschullat J. Arsenic in the geosphere-a review. Sci Total Environ. 2000;249(1-3):297-312.
5. Sheehy JW, Jones JH. Assessment of arsenic exposures and controls in gallium arsenide production. Am Ind Hyg Assoc J.1993;54:61-69.
6. Soucy NV, Ihnat MA, Kamat CD,et al. Arsenic stimulates angiogenesis and tumorigenesis in vivo. Toxicol Sci.2003; 76(2):271-279.
7. Sun G, Li X,Pi J, et al. Current research problems of chronic arsenieosis in China. J Heaith Popul Nutr.2006; 24(2):176-181.
8.杨克敌主编.微量元素与健康.北京：科学出版社(医学出版分社).2002：295-300.
9.朗胜喜.砷及其化合物的职业危害.中国城乡企业卫生.2005；109(5)：24-25.
10. Alonso FT, Garmendia ML, Bogado ME. Increased skin cancer mortality in Chile beyond the effect of ageing:Temporal analysis 1990 to 2005. Acta Derm Venereol.2010;90(2):141-146.
11. Celik I, Gallicchio L, Boyd K, Lam TK, Matanoski G, Tao X, et al. Arsenic in drinking water and lung cancer:a systematic review. Environ Res. 2008;108(1):48-55.
12. Chen CL, Chiou HY, Hsu LI, Hsueh YM, Wu MM, Wang YH, et al. Arsenic in drinking water and risk of urinary tract cancer:a follow-up study from northeastern Taiwan. Cancer Epidemiol Biomarkers Prev.2010;19(1):101-110.
13. Meliker JR, Slotnick MJ, AvRuskin GA, Schottenfeld D, Jacquez GM, Wilson ML, et al. Lifetime exposure to arsenic in drinking water and bladder cancer:a population-based case-control study in Michigan, USA. Cancer Causes Control.2010;21(5):745-757.
14. Morales KH, Ryan L, Kuo TL, Wu MM, Chen CJ. Risk of internal cancers from arsenic in drinking water. Environ Health Perspect.2000;108(7):655-661.
15. Smith AH, Hopenhayn-Rich C, Bates MN, Goeden HM, Hertz-Picciotto I, Duggan HM, et al. Cancer risks from arsenic in drinking water. Environ Health Perspect.1992;97:259-267.
16. IARC. International Agency for Research on Cancer Special Report:Policy, Vol.10, A review of human carcinogens-Part C:Metals, arsenic, dusts, and fibres, Lancet Oncol.2009; 10,453-455.
17. Chen CJ, Wang SL, Chiou JM, et al, Arsenic and diabetes and hypertension in human populations:a review. Toxicol Appl Pharmacol.2007;222(3):298-304.
18. Tseng GH, Tai TY, Chong CK, et al. Long-term arsenic exposure and incidence of noninsulin dependent diabetes mellitus:A cohort study in arsenicosis hyperendemic villages in Taiwan. Environ Health Perspect. 2000; 108:847-851.
19. Tokar EJ, Benbrahin-Tallaa L, Ward JM, et al. Cancer in experimental animals exposed to arsenic and arsenic compounds. Critical Rev Toxicol. 2010;40:912-927.
20. Waalkes MP, Liu J, Diwan,BA. Transplacental arsenic carcinogenesis in mice. Toxicol Appl Pharmacol.2007; 222:271-280.
21. Carter DE, Aposhian HV, Gandolfi AJ. The metabolism of inorganic arsenic oxides, gallium arsenide, and arsine:A toxicochemical review. Toxicol Appl Pharmacol.2003;193:309-334.
22. Tokar EJ, Diwan BA, Waalkes MP. Arsenic exposure in utero and non-epidermal proliferative response in Tg.AC mice. Int J Toxicol. 2010;118:108-115.
23. Waalkes MP, Liu J, Ward JM, et al. Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen. Toxicol Appl Pharmacol.2006; 215:295-305.
24. Waalkes MP, Liu J, Ward JM, et al. Urogenital carcinogenesis in female CD1 mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment. Cancer Res.2006;66:1337-1345.
25. Waalkes MP, Ward JM, Diwan BA. Induction of tumors of the liver, lung, ovary and adrenal in adult mice after brief maternal gestational exposure to inorganic arsenic:promotional effects of postnatal phorbol ester exposure on hepatic and pulmonary, but not dermal cancers. Carcinogenesis.2004; 25:133-141.
26. Waalkes MP, Ward JM, Liu J, et al. Transplacental carcinogenicity of inorganic arsenic in the drinking water:induction of hepatic, ovarian, pulmonary and adrenal tumors in mice. Toxicol Appl Pharmacol.2003; 186:7-17.
27. Anderson LM. Predictive values of traditional animal bioassay studies for human perinatal carcinogenesis risk determination. Toxicol Appl Pharmacol. 2004;199:162-174.
28. Anderson LM, Diwan BA, Fear NT, et al. Critical windows of exposure for children's health:cancer in human epidemiological studies and neoplasms in experimental animal models. Environ. Health Perspect.2000;108:573-594.
29. Birnbaum, LS, Fenton SE. Cancer and developmental exposure to endocrine disruptors. Environ Health Perspect.2003; 111:389-394.
30. Polyak K, Hahn WC. Roots and stems:stem cells in cancer. Nat.Med.2005; 11:296-300.
31. Singh SK, Clarke ID, Hide T, et al. Cancer stem cells in nervous system tumors. Oncogene.2004; 23(43):7267-7273.
32. Singh SK, Clarke ID, Terasaki M, et al. Identification of acancer stem cell in human brain tumors. Cancer Res.2003; 63(18):5821-5828.
33. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature.2004; 432(7015):396-401.
34. Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA.2003; 100(25):15178-15183.
35. Richardson D, Robson CN, Lang SH, et al. CD 133, a novel marker for human prostatic epithelial stem cells. J Cell Sci.2004; 117 (Pt 16):3539-3545.
36. Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res.2005; 65(23): 10946-10951.
37. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA.2003; 100(7):3983-3988.
38. Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65(13):5506-5511.
39. Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell.2005; 8(4):323-335.
40. Perez-Losada J, Balmain A. Stem-cell hierarchy in skin cancer. Nat Rev Cancer.2003; 3(6):434-443.
41. Seigel GM, Campbell LM, Narayan M, et al. Cancer stem cell characteristics in retinoblastoma. Mol Vis.2005; 11:729-737.
42. Li C, Heidt DQ Mollenberg N, et al. Identification of pancreatic cancer stem cells. Pancreas.2005; 31(4):452.
43. Fiegel HC, Gluer S, Roth B, et al. Stem-like cells in human hepatoblastoma. J Histochem Cytochem.2004; 52(11):1495-1501.
44. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science.2004; 306(5701):1568-1571.
45. Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer.Cell.2005; 121(6):823-835.
46. Setoguchi T, Taga T, Kondo T. Cancer stem cells persist in many cancer cell lines. Cell Cycle.2004; 3(4):414-415.
47. Patrawala L, Calhoun T, Schneider-Broussard R, et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2 —cancer cells are similarly tumorigenic. Cancer Res.2005; 65(14):6207-6219.
48. Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA.2004; 101(3):781-786.
49. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer.2003; 3:895-902.
50. Polyak K, Hahn WC. Roots and stems:stem cells in cancer. Nat Med. 2005; 11:296-300.
51. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumors:accumulating evidence and unresolved questions. Nat. Rev. Cancer.2008; 8:755-768.
52. Wicha MS, Liu S, Dontu G. Cancer stem cells:An old idea a paradigm shift. Cancer Res.2006;66:1883-1890.
53. Bomken S, Fiser K, Heidenreich O, et al. Understanding the cancer stem cell. Br J Cancer.2010; 103:439-445.
54. Lobo NA, Shimono Y, Qian D, et al. The biology of cancer stem cells. Annu Rev Cell Dev Biol.2007;23:675-699.
55. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature.2001;414:105-111.
56. Kelly PN, Dakic A, Adams JM, et al. Tumor growth need not be driven by rare cancer stem cells. Science.2007; 317:337.
57. Rosen JM, Jordan CT. The increasing complexity of the cancer stem cell paradigm. Science.2009;324:1670-1673.
58. O'Brien CA, Kreso A, Jamieson CHM. Cancer stem cells and self-renewal. Clin Cancer Res.2010; 16:3113-3120.
59. Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993;9:138-141.
60. Biedermann KA, Landolph JR. Induction of anchorage independence in human diploid fore skin fibroblasts by carcinogenic metal salts. Cancer Res. 1987; 47:3815-3823.
61. Kakunaga T, Yamaski H. Transformation assay of established cell lines: mechanisms and application, Chapter 5:Neoplastic transformation in cell cultures:IN-VITRO/IN-VIVO correlations. International Agency for Research on Cancer scientific publications No.67.1985.
62. Gildea JJ, Golden WL, Harding MA, et al. Genetic and phenotypic changes associated with the acquisition of tumorigenicity in human bladder cancer. Genes Chromosomes Cancer.2000;27(3):252-263.
63. Lodish H, Berk A, Zipursky SL, et al. Molecular cell biology, Chapter 24: Cancer. WH Freeman and Company.1999; fourth edition.
64. Hart I, Hogg N. Cell adhesion and cancer, Chapter 8:Adherens junction proteins in tumor progression, Cold Spring Harbor Laboratory Press.1995.
65. Starr C, Taggart R. Biology:The Unity and Diversity of Life,5/e, Chapter 17:Control of gene expression. Wadsworth Publishing Company.1998.
66. Shilkaitis A, Green A, Steele V, et al. Neoplastic transformation of mammary epithelial cells in rats is associated with decreased apopt otic cell death, Carcinogenesis.2000; 21:227-233.
67. Zhao CQ, Young MR, Diwan BA, et al. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci USA.1997; 94(20):10907-10912.
68. Romach EH, Zhao CQ, Del Razo LM, et al. Studies on the mechanisms of arsenic-induced self tolerance developed in liver epithelial cells through continuous low-level arsenite exposure. Toxicol Sci.2000;54(2):500-508.
69. Sens DA, Park S, Gurel V, et al. Inorganic cadmium- and arsenite-induced malignant transformation of human bladder urothelial cells. Toxicol Sci.2004; 79(1):56-63.
70.胡宇,金喜梅,王国荃,等.砷诱导NIH3T3细胞转化模型的建立.新疆医科大学学报.2004；27(1)：1-5.
71. Wen G, Calaf GM, Partridge MA, et al. Neoplastic transformation of human small airway epithelial cells induced by arsenic. Mol Med.2008; 14(1-2):2-10.
72. Li Y, Ling M, Xu Y, et al. The Repressive Effect of NF-kB on p53 by Mot-2 Is Involved in Human Keratinocyte Transformation Induced by Low Levels of Arsenite. Toxicol sci.2010; 116(1):174-182.
73. Ouyang W, Luo W, Zhang D, et al. PI-3K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation. Environ Health Perspect.2008; 116(1):1-6.
74.孔贵范,曲龙.砷的分子作用机制研究现状与展望.中国地方病学杂志.2003;22：13-16.
75. Menendez D, Mora G, Salazar AM,et al. ATM status confers sensitivity to arsenic cytotoxic effects. Mutagenesis.2001; 16:443-844.
76. Yoda A, Toyoshima K, Watanabe Y, et al. Arsenic Trioxide Augments Chk2/p53-mediated Apoptosis by Inhibiting Oncogenic Wip1 Phosphatase. J Biol Chem.2008; 283(27):18969-18979.
77.Takahashi M, Ota A, Karnan S, et al. Arsenic trioxide prevents nitric oxide production in lipopolysaccharide -stimulated RAW 264.7 by inhibiting a TRIF-dependent pathway. Cancer Sci.2012;doi:10.1111/cas.12053.
78. Xia J, Li YJ, Yang QL, et al. Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer. Int. J. Mol. Sci.2012; 13:9627-9641.
79. Lau A, Whitman SA, Jaramillo MC, et al. Arsenic-Mediated Activation of the Nrf2-Keapl Antioxidant Pathway. J Biochem Mol Toxicol.2012; 27, doi: 10.1002/jbt.21463.
80. Zhang Z, Wang X, Cheng S, et al. Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/(3-catenin pathway in human colorectal adenocarcinoma DLD1 cells. Toxicol Appl Pharmacol.2011; 256(2):114-121.
81. Hayashi T, Hideshima T, Akiyama M, et al. Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow micro-environment. Mol Cancer Ther.2002; 1:851-860.
82. Qu W, Bortner CD, Sakurai T,et al. Acquisition of apoptotic resistance in arsenic-induced malignant transformation:role of the JNK signal transduction pathway. Carcinogenesis.2002;23(1):151-159.
83. Pei B, Wang S, Guo X, et al. Arsenite-induced germline apoptosis through a MAPK-dependent,p53-independent pathway in Caenorhabditis elegans. Chem Res Toxicol.2008; 21(8):1530-1535.
84. Li JP, Yang JL. Cyclin B1 proteolysis via p38 MAPK signaling participatesin G2 checkpoint elicited by arsenite. J Cell Physiol.2007; 212(2):481-488.
85. Thorsen M, Di Y, Tangemo C, et al. The MAPK Hoglp modulates Fpslp-dependent arsenite uptake and tolerance in yeast. Mol Biol Cell. 2006;17(10):4400-4410.
86. Lau AT, Li M, Xie R, et al. Opposed arsenite-induced signaling pathways promote cell proliferation or apoptosis in cultured lung cells. Carcinogenesis. 2004;25(1):21-28.
87. Dong Z. The molecular mechanisms of arsenic-induced cell transformation and apoptosis. Environ Health Perspect.2002; 5:757-759.
88. Huang C, Ma WY, Li J, et al. Requirement of Erk, but not JNK, for arsenite-induced cell apoptosis. Environ Health Perspect.2002; 5:757-759.
89. He XQ, Chen R, Yang P, et al. Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK 1/2 in human embryo lung fibroblast cells. Toxicol Appl Pharmacol.2007; 220(1): 18-24.
90. Sakon S, Xue X, Takekawa M,et al. NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. Embo J.2003; 22(15):3898-3909.
91. Karin M. NF-kappaB and cancer:mechanisms and targets. Mol Carcinog. 2006; 45(6):355-361.
92. Bode AM, Dong Z.The paradox of arsenic:molecular mechanisms of cell transformation and chemotherapeutic effects. Crit Rev Oncol Hematol, 2002;42(1):5-24.
93. Jomova K, Jenisova Z, Feszterova M, et al. Arsenic:toxicity, oxidative stress and human disease. J.Appl.Toxicol.2011;31:95-107.
94. Leonidas C. Platanias. Biological Responses to Arsenic Compounds. J Bio Chem.2009,284(28):18583-18587.
95.邓芙蓉,李艳宏,张华明,等.NaAsO2和氧苯胂对人皮肤成纤维细胞缝隙连接通讯的动态影响及作用特征.中国药理学与毒理学杂志,2002；16(5)：378-381.
96. Deng FR, Jin Y, Wang H, et al. Phenylarsine oxide inhibits gap junctional intercellular communication between human skin fibroblast cells and damages cellular DNA. J Hyg Res.2002; 31(3):151-153.
97. Fry RC, Navasumrit P, Valiathan C, et al. Activation of inflammation/NF-κB signaling in infants born to arsenic-exposed mothers. PLoS Genet.2007,3:e207.
98. Maria A, Muhammad G. Kibriya, et al. Gene Expression Profiles in Peripheral Lymphocytes by Arsenic Exposure and Skin Lesion Status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006;15:1367-1375.
99. Dower SK, Qwarnstrom EE, Page RC, et al. Biology of the interleukin-1 receptor. J Invest Dermatol.1990;94:68-73S.
100. Labow M, Shuster D, Zetterstrom M, et al. Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice.J Immunol. 1997;159:2452-2461.
101. Takami Y, Motoki T, Yamamoto I, et al. Synergistic induction of hepatocyte growth factor in human skin fibroblasts by the inflammatory cytokines interleukin-1 and interferong. Biochem Biophys Res Commun. 2005;327:212-217.
102. Liu Q, Zhang H, Smeester L, et al. The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med. Genomics.2010; 3:37.
103. Mo J, Xia Y, Wade TJ. Altered Gene Expression by Low-Dose Arsenic Exposure in Humans and Cultured Cardiomyocytes:Assessment by Real-Time PCR Arrays. Int J Environ Res Public Health.2011; 8:2090-2108.
104. Shi H, Shi X, Liu KJ. Oxidative mechanism of arsenic toxicity and carcinogenesis. Mol Cell Biochem.2004;255:67-78.
105. Cohen SM, Arnold LL, et al. Methylated arsenicals:the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Crit Rev Toxicol.2006; 36:99-133.
106. Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress.Curr Med Chem.2005;12:1161-1208.
107. Flora SJS, Bhadauria S, Kannan GM,et al. Arsenic induced oxidative stress and the role of antioxidant supplementation during chelation:a review. J Environ Biol.2007;28:333-347.
108. Applegate LA, Luscher P, Tyrrell RM. Induction of heme oxygenase:a general response to oxidant stress in cultured mammalian cell. Cancer Res.1991;51:974-978.
109. Hei Tk, Liu SX, Waldren C. Mutagenicity of arsenic in mammalian cells: Role of reactive oxygen species. Proc Natl Acad Sci USA.1998;95:8103-8107.
110. Liu SX, Athar M, Lippai I,et al. Induction of oxyradicals by arsenic: Implication for mechanism of genotoxicity. Proc Natl Acad Sei USA. 2001;98:1643-1648.
111. Ahmad S, Kichin KT, Cullen WR. Arsenic species that cause release of iron from ferritin and generation of activated oxygen. Areh Biochem BioPhys.2000;382:195-202.
112.刘力.DNA氧化损伤的修复及其与致癌的关系.中华劳动卫生职业病杂志,1999,17：181-183.
113. Matsui M, Nishigori C, Toyokuni S, et al. The role of oxidative DNA damage in human arsenic carcinogenesis:detection of 8-hydnxy-2-deoxyguanosine in arsenic-related Bowen's disease. The Journal of Investigative Dermatology,1999; 113:26-31.
114. Wanibuchi H, Hori T, Meenakshi V,et al. Promotion of rat hepatocarcinogenesis by dimethylarsinic acid:association with elevated ornithine decarboxylase activity and formation of 8-hydroxydeoxyguanosine in the liver. JPn J Caneer Res.1997;88:1149-1154.
115. Vijayaraghavan M, Wanibuchi H, Karim R, et al. Dimethylarsinic acid induces 8-hydroxy-2'-deoxyguanosine formation in the kidney of NCI-Black-Reiter rats. Cancer Lett.2001;165(1):11-17.
116.李达圣.应用单细胞凝胶电泳比较研究砷对人类DNA的损伤.中国地方病学杂志.2001；20：212-216.
117. Yamanaka K, Hasegawa A, Sawamura R,et al. Cellular response to oxidative damage in lung induced by the administration of dimethylarsinic acid, a major metabolite of inorganic arsenics, in mice. Toxicol Appl Pharmacol. 1991;108(2):205-213.
118. Brown JL, Kitchin KT. Arsenite,but not cadmium,induces ornithine decarboxylase and heme oxygenase in rat liver:relevance to arsenic careinogenesis. Caneer Lett.1996;98:227-331.
119. Germolec DR, Spalding J, Booman GA. Arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors. Mutat Res.1997;386(3):209-218.
120. Kitchin KT, Recent advance in arsenic carcinogenesis:modes of action, animal model system, and methylated arsenic metabolites. Toxic and Appl Pharmacol.2001; 172:249-261.
121.顾军,毕新岭.砷剂与角质形成细胞及其致癌机制的研究进展.国外医学皮肤性病学分册.2001；27(3)：150-152.
122. Abemathy CO, Liu YP, Longfellow D, et al. Arsenic:Health effects, mechanisms of actions, and research issues. Environ Health Perspect.1999;107:593-600.
123. Hamadeh HK, Vargas M, Lee E, et al. Arsenic disrupts cellular levels of P53 and mdm2:A potential mechanism of carcinogenesis. Biochem Biophys Res Commun.1999;263:446-449.
124. Salazar AM. Induction of p53 protein expression by sodium arsenite. Mutat Res.1997;381:259-265.
125. Mass MJ, Wang L. Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene P53 in human lung cells:A model for a mechanism of a carcinogenesis. Mutat Res.1997;263:446-449.
126. Patterson TJ, Reznikova TV, Phillips MA, et al. Arsenite maintains germinative state in cultured human epidermal cells. Toxicol Appl Pharmacol. 2005;207:69-77.
127. Patterson TJ, Rice RH. Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. Toxicol Appl Pharmacol.2007; 221:119-128.
128. Waalkes MP, Liu J, Germolec DR, et al. Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics. Cancer Res.2008; 68,8278-8285.
129. Tokar EJ, Qu W, Liu J, et al. Arsenic-specific stem cell selection during malignant transformation. J Natl Cancer Inst.2010; 102,638-649.
130. Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature.2006;442:818-822.
131. Dubrovska A, Kim S, Salamone RJ, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA.2009;106(1):268-273.
132. Groszer M, Erickson R, Scripture-Adams DD, et al. PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. Proc Natl Acad Sci USA.2006; 103(1):111-116.
133. Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukemia-initiating cells. Nature.2006; 441:475-482.
134. Sell S. Cancer stem cells and differentiation therapy. Tumor Biol.2006; 27:59-70.
135. Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature.2004;432:324-331.
136.Tokar EJ, Diwan BA, Waalkes MP. Arsenic exposure transforms human epithelial stem/progenitor cells into a cancer stem-like phenotype. Environ Health Perspect.2010;118(1):108-115.
137. Liaw J, Marshall G, Yuan Y, et al. Increased childhood liver cancer mortality and arsenic in drinking water in Northern Chile. Cancer Epidemiol Biomarkers Prev.2008;17:1982-1987.
138. Marshall G, Ferreccio C, Yuan Y, et al. Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water. J Natl Cancer Inst. 2007; 99:920-928.
139. Smith AH, Marshall G, Yuan Y, et al. Increased mortality from lung cancer and bronchiectasis in young adults after exposure to arsenic in utero and early childhood. Environ Health Perspect.2006; 114:1293-1296.
140. Yuan Y, Marshall G, Ferreccio C, et al. Kidney cancer mortality:fifty-year latency patterns related to arsenic exposure. Epidemiology.2010;21:103-108.
141. Yorifuji T, Tsuda T, Grandjean P. Unusual cancer excess after neonatal arsenic exposure from contaminated milk powder. J Natl Cancer Inst. 2010;102:360-361.
142. Aposhian HV, Zakharyan RA, Avram MD, et al. A review of the enzymology of arsenic metabolism and a new potential role of hydrogen peroxide in the detoxication of the trivalent arsenic species. Toxicol Appl Pharmacol.2004;198(3):327-335.
143. Suzuki KT, Mandal BK, Ogra Y.Speciation of arsenic in body fluids.Talanta.2002;58(1):111-119.
144. Naranmandura H, Suzuki N, Iwata K, et al. Arsenic metabolism and thioarsenicals in hamsters and rats. Chem Res Toxicol.2007;20(4):616-624.
145. Wanibuchi H, Salim EI, Kinoshita A,et al.Understanding arsenic carcinogenicity by the use of animal models.Toxicol Appl Pharmacol. 2004;198(3):366-376.
146. Soltysova A, Altanerova V, Altaner C. Cancer stem cells. Neoplasma. 2005;52(6):435-440.
147. S Huang, S Guo, F Guo, et al. CD44v6 expression in human skin keratinocytes as a possible mechanism for carcinogenesis associated with chronic arsenic exposure. European Journal of Histochemistry.2012; 57:el.
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