乙酰肝素酶调节胃癌细胞功能及其基因表达谱变化研究
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摘要
目的
探讨乙酰肝素酶(heparanase, HPSE)基因对胃癌细胞生物学行为的影响；阐明HPSE基因在胃癌细胞信号转导、生长发育、炎症反应及肿瘤转移等多项生物过程中的可能分子机制
方法
1 siRNA对胃癌细胞乙酰肝素酶基因表达及其生物学行为的影响
①应用RT-PCR技术筛选HPSE基因高表达的胃癌细胞株。②设计、合成反义寡脱氧核苷酸(AS-ODN)及对照寡脱氧核苷酸(NS-ODN),转染高表达HPSE基因的胃癌细胞株,利用Real-Time PCR技术确定沉默效果最佳的siRNA浓度,并运用Real-Time PCR和Western Blot技术分别在mRNA和蛋白水平验证对HPSE基因表达的沉默效果。③应用透射电镜观察HPSE siRNA对胃癌细胞SGC-7901形态学的影响；采用Annexin V-FITC/PI双染流式细胞术检测HPSE siRNA对胃癌细胞SGC-7901凋亡的影响。④应用Matrigel侵袭实验和细胞迁移实验研究HPSE siRNA对胃癌细胞SGC-7901侵袭力和迁移能力的影响。2乙酰肝素酶反义寡核苷酸对胃癌细胞基因表达谱的影响
应用Affymetrix Human U133 Plus2基因芯片技术,分别提取siRNA抑制HPSE基因表达前后胃癌细胞SGC-7901的总RNA,反转录成cDNA,进一步荧光标记后进行芯片杂交,杂交结果经扫描及软件分析,最后Ratio值为Cy3/Cy5(即实验组／对照组)。差异基因筛选标准为正标Ratio(Cy3/Cy5)≥2,同时反标Ratio(Cy3/Cy5)≤0.5.分析siRNA抑制HPSE基因表达后,胃癌细胞中受HPSE调控的下游基因表达谱的变化,并且部分上调及下调基因的表达水平用Real-Time PCR进行了验证。对于差异表达在2倍以上的基因,我们利用博奥公司的MAS3.0分析软件进行了GO分析,并对差异表达在1.5倍以上的基因进行了Pathway分析。
结果
1 siRNA对胃癌细胞乙酰肝素酶基因表达及其生物学行为的影响
①RT-PCR技术检测胃癌细胞株中HPSE基因表达情况,结果显示SGC-7901细胞表达HPSE最高,故选用SGC-7901细胞为实验细胞模型。②RT-PCR技术及Real-Time PCR实验证实沉默效果最好的siRNA浓度为10 nM。③Real-Time PCR及Western Blot检测：相对于阴性对照NC组(无义siRNA对照组),siRNA沉默组的HPSE基因的mRNA水平和蛋白表达量显著降低。④siRNA沉默HPSE基因后,透射电镜结果显示胃癌细胞SGC-7901形态学发生典型的凋亡现象；Annexin V-FITC/PI双染流式细胞术检测发现凋亡细胞明显增多,由正常细胞的1.58%升高为8.45%。⑤Transwell细胞侵袭实验结果显示,siRNA沉默HPSE基因后的胃癌细胞SGC-7901侵袭到Transwell膜后面的细胞数较阴性对照组显著减少(P<0.01),表明HPSE基因沉默明显降低胃癌细胞的侵袭能力。利用细胞划痕实验检测细胞的迁移能力,结果显示,HPSE基因沉默的胃癌细胞在划痕后24h、36h的宽度明显大于对照组(P<0.05),表明抑制HPSE基因可明显降低胃癌细胞的迁移能力。
2乙酰肝素酶反义寡核苷酸对胃癌细胞基因表达谱的影响
Affymetrix芯片结果表明,siRNA沉默HPSE基因后,胃癌细胞SGC7901中VEGF信号通路的中心介导分子PRKCA和PRKCB的表达明显下降；介导VEGFR-2通路的锚定蛋白SHB、VEGFR-2的相互作用蛋白VE-cadherin、炎症因子IL-1a／IL-1b表达下降,介导天然免疫的分子DEFB1、黏附分子CD44表达升高。
结论
1 siRNA沉默HPSE基因后,降低胃癌细胞SGC-7901的侵袭和迁移能力；
2 siRNA沉默HPSE基因表达后,胃癌细胞SGC-7901中VEGF信号通路的中心介导分子PRKCA和PRKCB的及传递该通路信号的重要分子SHB和VE-cadherin表达均下降,但跨膜糖蛋白CD44表达升高,这些分子改变可能共同参与了HPSE干涉后的血管生成抑制过程。
3 siRNA沉默HPSE基因后,SHB、VE-cadherin表达下降,CD44表达升高,FAK通路受到抑制,这些因素可能共同作用导致胃癌细胞SGC-7901的凋亡增加。
4 siRNA沉默HPSE基因后,炎症因子IL-1a／IL-1b表达下降、能抑制炎症反应的CD44黏附分子表达增加以及炎症负调控因子HO-1表达增加,可能共同参与HPSE干涉后对炎症反应的抑制作用。
Object:To investigate the impact of heparanase(HPSE) gene on gastric cancer biological behaviors and clarify the underlying molecular mechanisms of HPSE gene in many biological processes of the gastric cancer cells such as signal transduction, tumor angiogenesis, inflammation and tumor metastasis.
Methods:
1 Effects of HPSE siRNA on HPSE gene expression and biological behaviors of gastric cancer cells
①RT-PCR was performed to screen gastric cancer cell lines with high HPSE gene expression.②Both of antisense oligodeoxyribonucleotide (AS-ODN) and control oligodeoxyribonucleotide (NS-ODN) targeting HPSE were designed and chemically synthesized. The screened gastric cancer cells were transfected with optical concentration of AS-ODN and NS-ODN tested by Real-Time PCR, and expression of HPSE at mRNA and protein levels were examined by Real-Time PCR and Western Blot in order to verify the silencing effects.③Effects of silencing HPSE on the morphology of gastric cancer cell SGC-7901 were observed by transmission electron microscope (TEM). The role of silencing HPSE on apoptosis of gastric cancer cell was detected by Annexin V-FITC/PI flow cytometry.④Effects of silencing HPSE on the abilities of invasiveness and migration of gastric cancer cell SGC-7901 were tested by Matrigel invasion assay and cell migration assay.
2 Effects of HPSE antisense oligonucleotides on gene expression profiling of gastric cancer cells
Affymetrix Human U133 Plus2 gene chips were used to identify the gene expression changes after HPSE expression knockdown. Total RNA extracted from gastric cancer cells with AS-ODN and NS-ODN was reversely transcripted into cDNA to make chip cross-fertilization after fluorescent labeling. The cross-fertilization results were scanned and analyzed by software and then the Ratio was recorded as Cy3/Cy5 (case group/control group). The screening standards of differential gene were that positive Ratio(Cy3/Cy5)≥2 and negative Ratio (Cy3/Cy5)≤0.5. Some up and down regulated genes were verified by Real-Time PCR after HPSE expression was silenced and gene expression profiling changes of the HPSE-mediated downstream in gastric cancer cell were analyzed. Genes of differential expression that exceeded 2 folds were analyzed by "GO" tool using MAS3.0 software of CapitalBio Corporation, whereas genes that exceeded 1.5 folds were analyzed by "Pathway" tool.
Results:
1 Effects of HPSE silencing on HPSE gene expression and biological behavior of gastric cancer cells
①RT-PCR detection showed that SGC-7901 expressed the highest HPSE levels among three gastric cancer cell lines, that's why SGC-7901 was selected as experiment cell model.②The optimal concentration of siRNA, verified by RT-PCR and Real-Time PCR assay, was lOnM.③Real-Time PCR and Western Blot results showed that expression of HPSE at mRNA and proteins level after siRNA decreased significantly as compared with negative control group.④TEM observation showed that HPSE silenced SGC-7901 exhibited typical apoptosis cell morphology. Annexin V/PI flow cytometry analysis showed that apoptosis was increased remarkably from 1.58% in mock group to 8.45% in HPSE silenced group.⑤Transwell assay indicated that the number of cell migrated through membrane in HPSE silenced group were more less than that of mock group (P<0.01), suggesting that inhibition of HPSE expression could abolish the invasive capabilities of SGC-7901 cells. Scrape migration assay showed that the wounded empty space in HPSE silenced group was obviously wider than that of control group at 24h and 36h after being scraped (P<0.05), indicating that inhibition of HPSE could decrease the migration ability of gastric cancer cells obviously.
2 Effects of silencing HPSE on down stream gene expression of gastric cancer cells
Affymetrix analysis showed that expression of PRKCA and PRKCB, central mediator molecule of VEGF signal pathway, was decreased significantly in HPSE silenced group compared with mock group. Meanwhile, the expression of SHB, an adaptor protein of VEGFR-2 pathway, and VE-cadherin which interacted with VEGFR-2, were decreased in HPSE silenced group. It is also founded the inflammatory factor IL-la/IL-lb decreased. However, expressions of innate immunity-mediating molecule DEFB1 and adhesion molecule CD44 increased when HPSE were inhibited.
Conclusions:
1 Silencing HPSE abolished the abilities of invasion and migration of SGC-7901;
2 Expressions of PRKCA and PRKCB, central bridge molecule of VEGF signal cascades, and that of SHB and VE-cadherin, both of which were important member of this pathway, were decreased in HPSE silenced group. Meanwhile, the expression of transmembrane glycoprotein CD44 was increased. These changes might play an important role in the decreased angiogenesis when HPSE expression was attenuated;
3 Gene Chip assay showed that decreased expressions of SHB and VE-cadherin, increased expression of CD44, and attenuated FAK pathway when HPSE expression was silenced. All of these might be responsible for increasing cell apoptosis after HPSE was silenced;
4 Gene Chip assay also exhibited that decreased expression of inflammatory factor IL-1a/IL-1b, increased expression of anti-inflammation adhesion molecule CD44 and negative inflammation regulatory factor HO-1 in HPSE silenced group relative to mock group. All of these might be involved in the inhibition of inflammatory reaction after HPSE was silenced.
探讨乙酰肝素酶(heparanase, HPSE)基因对胃癌细胞生物学行为的影响；阐明HPSE基因在胃癌细胞信号转导、生长发育、炎症反应及肿瘤转移等多项生物过程中的可能分子机制
方法
1 siRNA对胃癌细胞乙酰肝素酶基因表达及其生物学行为的影响
①应用RT-PCR技术筛选HPSE基因高表达的胃癌细胞株。②设计、合成反义寡脱氧核苷酸(AS-ODN)及对照寡脱氧核苷酸(NS-ODN),转染高表达HPSE基因的胃癌细胞株,利用Real-Time PCR技术确定沉默效果最佳的siRNA浓度,并运用Real-Time PCR和Western Blot技术分别在mRNA和蛋白水平验证对HPSE基因表达的沉默效果。③应用透射电镜观察HPSE siRNA对胃癌细胞SGC-7901形态学的影响；采用Annexin V-FITC/PI双染流式细胞术检测HPSE siRNA对胃癌细胞SGC-7901凋亡的影响。④应用Matrigel侵袭实验和细胞迁移实验研究HPSE siRNA对胃癌细胞SGC-7901侵袭力和迁移能力的影响。2乙酰肝素酶反义寡核苷酸对胃癌细胞基因表达谱的影响
应用Affymetrix Human U133 Plus2基因芯片技术,分别提取siRNA抑制HPSE基因表达前后胃癌细胞SGC-7901的总RNA,反转录成cDNA,进一步荧光标记后进行芯片杂交,杂交结果经扫描及软件分析,最后Ratio值为Cy3/Cy5(即实验组／对照组)。差异基因筛选标准为正标Ratio(Cy3/Cy5)≥2,同时反标Ratio(Cy3/Cy5)≤0.5.分析siRNA抑制HPSE基因表达后,胃癌细胞中受HPSE调控的下游基因表达谱的变化,并且部分上调及下调基因的表达水平用Real-Time PCR进行了验证。对于差异表达在2倍以上的基因,我们利用博奥公司的MAS3.0分析软件进行了GO分析,并对差异表达在1.5倍以上的基因进行了Pathway分析。
结果
1 siRNA对胃癌细胞乙酰肝素酶基因表达及其生物学行为的影响
①RT-PCR技术检测胃癌细胞株中HPSE基因表达情况,结果显示SGC-7901细胞表达HPSE最高,故选用SGC-7901细胞为实验细胞模型。②RT-PCR技术及Real-Time PCR实验证实沉默效果最好的siRNA浓度为10 nM。③Real-Time PCR及Western Blot检测：相对于阴性对照NC组(无义siRNA对照组),siRNA沉默组的HPSE基因的mRNA水平和蛋白表达量显著降低。④siRNA沉默HPSE基因后,透射电镜结果显示胃癌细胞SGC-7901形态学发生典型的凋亡现象；Annexin V-FITC/PI双染流式细胞术检测发现凋亡细胞明显增多,由正常细胞的1.58%升高为8.45%。⑤Transwell细胞侵袭实验结果显示,siRNA沉默HPSE基因后的胃癌细胞SGC-7901侵袭到Transwell膜后面的细胞数较阴性对照组显著减少(P<0.01),表明HPSE基因沉默明显降低胃癌细胞的侵袭能力。利用细胞划痕实验检测细胞的迁移能力,结果显示,HPSE基因沉默的胃癌细胞在划痕后24h、36h的宽度明显大于对照组(P<0.05),表明抑制HPSE基因可明显降低胃癌细胞的迁移能力。
2乙酰肝素酶反义寡核苷酸对胃癌细胞基因表达谱的影响
Affymetrix芯片结果表明,siRNA沉默HPSE基因后,胃癌细胞SGC7901中VEGF信号通路的中心介导分子PRKCA和PRKCB的表达明显下降；介导VEGFR-2通路的锚定蛋白SHB、VEGFR-2的相互作用蛋白VE-cadherin、炎症因子IL-1a／IL-1b表达下降,介导天然免疫的分子DEFB1、黏附分子CD44表达升高。
结论
1 siRNA沉默HPSE基因后,降低胃癌细胞SGC-7901的侵袭和迁移能力；
2 siRNA沉默HPSE基因表达后,胃癌细胞SGC-7901中VEGF信号通路的中心介导分子PRKCA和PRKCB的及传递该通路信号的重要分子SHB和VE-cadherin表达均下降,但跨膜糖蛋白CD44表达升高,这些分子改变可能共同参与了HPSE干涉后的血管生成抑制过程。
3 siRNA沉默HPSE基因后,SHB、VE-cadherin表达下降,CD44表达升高,FAK通路受到抑制,这些因素可能共同作用导致胃癌细胞SGC-7901的凋亡增加。
4 siRNA沉默HPSE基因后,炎症因子IL-1a／IL-1b表达下降、能抑制炎症反应的CD44黏附分子表达增加以及炎症负调控因子HO-1表达增加,可能共同参与HPSE干涉后对炎症反应的抑制作用。
Object:To investigate the impact of heparanase(HPSE) gene on gastric cancer biological behaviors and clarify the underlying molecular mechanisms of HPSE gene in many biological processes of the gastric cancer cells such as signal transduction, tumor angiogenesis, inflammation and tumor metastasis.
Methods:
1 Effects of HPSE siRNA on HPSE gene expression and biological behaviors of gastric cancer cells
①RT-PCR was performed to screen gastric cancer cell lines with high HPSE gene expression.②Both of antisense oligodeoxyribonucleotide (AS-ODN) and control oligodeoxyribonucleotide (NS-ODN) targeting HPSE were designed and chemically synthesized. The screened gastric cancer cells were transfected with optical concentration of AS-ODN and NS-ODN tested by Real-Time PCR, and expression of HPSE at mRNA and protein levels were examined by Real-Time PCR and Western Blot in order to verify the silencing effects.③Effects of silencing HPSE on the morphology of gastric cancer cell SGC-7901 were observed by transmission electron microscope (TEM). The role of silencing HPSE on apoptosis of gastric cancer cell was detected by Annexin V-FITC/PI flow cytometry.④Effects of silencing HPSE on the abilities of invasiveness and migration of gastric cancer cell SGC-7901 were tested by Matrigel invasion assay and cell migration assay.
2 Effects of HPSE antisense oligonucleotides on gene expression profiling of gastric cancer cells
Affymetrix Human U133 Plus2 gene chips were used to identify the gene expression changes after HPSE expression knockdown. Total RNA extracted from gastric cancer cells with AS-ODN and NS-ODN was reversely transcripted into cDNA to make chip cross-fertilization after fluorescent labeling. The cross-fertilization results were scanned and analyzed by software and then the Ratio was recorded as Cy3/Cy5 (case group/control group). The screening standards of differential gene were that positive Ratio(Cy3/Cy5)≥2 and negative Ratio (Cy3/Cy5)≤0.5. Some up and down regulated genes were verified by Real-Time PCR after HPSE expression was silenced and gene expression profiling changes of the HPSE-mediated downstream in gastric cancer cell were analyzed. Genes of differential expression that exceeded 2 folds were analyzed by "GO" tool using MAS3.0 software of CapitalBio Corporation, whereas genes that exceeded 1.5 folds were analyzed by "Pathway" tool.
Results:
1 Effects of HPSE silencing on HPSE gene expression and biological behavior of gastric cancer cells
①RT-PCR detection showed that SGC-7901 expressed the highest HPSE levels among three gastric cancer cell lines, that's why SGC-7901 was selected as experiment cell model.②The optimal concentration of siRNA, verified by RT-PCR and Real-Time PCR assay, was lOnM.③Real-Time PCR and Western Blot results showed that expression of HPSE at mRNA and proteins level after siRNA decreased significantly as compared with negative control group.④TEM observation showed that HPSE silenced SGC-7901 exhibited typical apoptosis cell morphology. Annexin V/PI flow cytometry analysis showed that apoptosis was increased remarkably from 1.58% in mock group to 8.45% in HPSE silenced group.⑤Transwell assay indicated that the number of cell migrated through membrane in HPSE silenced group were more less than that of mock group (P<0.01), suggesting that inhibition of HPSE expression could abolish the invasive capabilities of SGC-7901 cells. Scrape migration assay showed that the wounded empty space in HPSE silenced group was obviously wider than that of control group at 24h and 36h after being scraped (P<0.05), indicating that inhibition of HPSE could decrease the migration ability of gastric cancer cells obviously.
2 Effects of silencing HPSE on down stream gene expression of gastric cancer cells
Affymetrix analysis showed that expression of PRKCA and PRKCB, central mediator molecule of VEGF signal pathway, was decreased significantly in HPSE silenced group compared with mock group. Meanwhile, the expression of SHB, an adaptor protein of VEGFR-2 pathway, and VE-cadherin which interacted with VEGFR-2, were decreased in HPSE silenced group. It is also founded the inflammatory factor IL-la/IL-lb decreased. However, expressions of innate immunity-mediating molecule DEFB1 and adhesion molecule CD44 increased when HPSE were inhibited.
Conclusions:
1 Silencing HPSE abolished the abilities of invasion and migration of SGC-7901;
2 Expressions of PRKCA and PRKCB, central bridge molecule of VEGF signal cascades, and that of SHB and VE-cadherin, both of which were important member of this pathway, were decreased in HPSE silenced group. Meanwhile, the expression of transmembrane glycoprotein CD44 was increased. These changes might play an important role in the decreased angiogenesis when HPSE expression was attenuated;
3 Gene Chip assay showed that decreased expressions of SHB and VE-cadherin, increased expression of CD44, and attenuated FAK pathway when HPSE expression was silenced. All of these might be responsible for increasing cell apoptosis after HPSE was silenced;
4 Gene Chip assay also exhibited that decreased expression of inflammatory factor IL-1a/IL-1b, increased expression of anti-inflammation adhesion molecule CD44 and negative inflammation regulatory factor HO-1 in HPSE silenced group relative to mock group. All of these might be involved in the inhibition of inflammatory reaction after HPSE was silenced.
引文
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[25]Takaoka M, Naomoto Y, Ohkawa T, et al. Heparanase expression correlates with invasion and poor prognosis in gastric cancers. Lab Invest.2003,83: 613-622.
[26]Inoue H, Mimori K, Utsunomiya T, et al. Heparanase expression in clinical digestive malignancies. Oncol Rep.2001,8(3):539-542.
[27]Xu X, Ding J, Ding H, et al. Immunohistochemical detection of heparanase-1 expression in eutopic and ectopic endometrium from women with endometriosis. Fertil Steril.2007,88(5):1304-1310.
[28]Tatro ET, Everall IP, Kaul M, et al. Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: implications for major depressive disorder. Brain Res.2009,1286(25):1-12.
[29]辛晓燕,毛敬,刘玉,等.siRNA抑制卵巢癌细胞株SKOV3 HPSE基因表 达的研究.中国肿瘤生物治疗杂志.2006,13(2)：124-128.
[30]李文才,孙淼淼,张红,等.肝素酶特异性RNAi对人食管癌EC9706细胞肝素酶基因表达的影响.郑州大学学报(医学版).2007,42(1)：9-11.
[31]熊震,汤旭东,房殿春,等.肝素酶RNAi对HepG2肝癌细胞生物学行为的影响.实用临床医药杂志.2008,12(1)：12-16.
[32]王霞,房静远.基因芯片技术在胃黏膜病变中的研究进展.国际消化病杂志.2007,27(3)：188-190.
[1]Yingying X, Yong Z, Zhenning W, et al. Role of heparanase-1 in gastric carcinoma invasion. Asian Pac J Cancer Prev.2009,10(1):151-154.
[2]Ou XL, Chen HJ, Sun WH, et al. Effects of angiopoietin-1 on attachment and metastasis of human gastric cancer cell line BGC-823. World J Gastroenterol. 2009,15(43):5432-5441.
[3]Tatro ET, Everall IP, Kaul M, et al. Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52:implications for major depressive disorder. Brain Res.2009,1286(25):1-12.
[4]Silva M, Azenha D, Pereira C, et al. Gastric carcinoma and chronic gastritis: epigenetic regulation of CDH1 (E-Cadherin), CDKN2A (p16INK4A), PTGS2 (COX-2) and EGFR genes through methylation. Acta Med Port.2010,23(1): 5-14.
[5]Okayama H, Kumamoto K, Saitou K, et al. CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer. Oncol Rep.2009,22(4):745-55.
[6]Ke JJ, Shao QS, Ling ZQ. Expression of E-selectin, integrin betal and immunoglobulin superfamily member in human gastric carcinoma cells and its clinicopathologic significance. World J Gastroenterol.2006,12(22):3609-3611.
[7]Carboni M, Guadagni S, Pistoia MA, et al. Chronic atrophic gastritis and risk of N-nitroso compounds carcinogenesis. Langenbecks Arch Chir.1988,373(2): 82-90.
[8]Stec-Michalska K, Peczek L, Michalski B, et al. Helicobacter pylori infection and family history of gastric cancer decrease expression of FHIT tumor suppressor gene in gastric mucosa of dyspeptic patients. Helicobacter.2009,14(5):126-134.
[9]Lee KH, Kim JR. Kiss-1 suppresses MMP-9 expression by activating p38 MAP kinase in human stomach cancer. Oncol Res.2009,18(2-3):107-116.
[10]Ohtawa Y, Naomoto Y, Shirakawa Y, et al. The close relationship between heparanase and cyclooxygenase-2 expressions in signet-ring cell carcinoma of the stomach. Hum Pathol.2006,37(9):1145-1152.
[11]Zheng LD, Jiang GS, Pu JR, et al. Stable knockdown of heparanase expression in gastric cancer cells in vitro. World J Gastroenterol.2009,15(43):5442-5448.
[12]Friand V, Haddad O, Papy-Garcia D, et al. Glycosaminoglycan mimetics inhibit SDF-1/CXCL12-mediated migration and invasion of human hepatoma cells. Glycobiology.2009,19(12):1511-1524.
[13]Teoh ML, Fitzgerald MP, Oberley LW, et al. Overexpression of extracellular superoxide dismutase attenuates heparanase expression and inhibits breast carcinoma cell growth and invasion. Cancer Res.2009,69(15):6355-6363.
[14]Haupt LM, Murali S, Mun FK, et al. The heparan sulfate proteoglycan (HSPG) glypican-3 mediates commitment of MC3T3-E1 cells toward osteogenesis. J Cell Physiol.2009,220(3):780-791.
[15]Yingying X, Yong Z, Zhenning W, et al. Role of heparanase-1 in gastric carcinoma invasion. Asian Pac J Cancer Prev.2009,10(1):151-154.
[1]Cohen I, et al. Heparanase promotes growth, angiogenesis and survival of primary breast tumors. Int J Cancer,2006,118(7):1609-1617.
[2]Edovitsky E, et al. Heparanase gene silencing, tumor invasiveness, angiogenesis, and metastasis. J Natl Cancer Inst,2004,96(16):1219-1230.
[3]Zcharia E, et al. Transgenic expression of mammalian heparanase uncovers physiological functions of heparan sulfate in tissue morphogenesis, vascularization, and feeding behavior. Faseb J,2004,18(2):252-263.
[4]Zcharia E, et al. Newly generated heparanase knock-out mice unravel co-regulation of heparanase and matrix metalloproteinases. PLoS One,2009, 4(4):5181.
[5]Funa NS, et al. Dysfunctional microvasculature as a consequence of shb gene inactivation causes impaired tumor growth. Cancer Res,2009,69(5): 2141-2148.
[6]Funa NS, et al. Shb gene knockdown increases the susceptibility of SVR endothelial tumor cells to apoptotic stimuli in vitro and in vivo. J Invest Dermatol,2008,128(3):710-716.
[7]Hauck CR, et al. FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. Embo J,2002,21(23): 6289-6302.
[8]Blaschuk OW, Devemy E. Cadherins as novel targets for anti-cancer therapy. Eur J Pharmacol,2009,625(1-3):195-198.
[9]Gory-Faure S, et al. Role of vascular endothelial-cadherin in vascular morphogenesis. Development,1999,126(10):2093-2102.
[10]Liao F, et al. Selective targeting of angiogenic tumor vasculature by vascular endothelial-cadherin antibody inhibits tumor growth without affecting vascular permeability. Cancer Res,2002,62(9):2567-2575.
[11]Ayers M, et al. Discovery and validation of biomarkers that respond to treatment with brivanib alaninate, a small-molecule VEGFR-2/FGFR-1 antagonist. Cancer Res,2007,67(14):6899-6906.
[12]Gotte M, Yip G.W. Heparanase, hyaluronan, and CD44 in cancers:a breast carcinoma perspective. Cancer Res,2006,66(21):10233-10237.
[13]Watanabe O, et al. Expression of a CD44 variant and VEGF-C and the implications for lymphatic metastasis and long-term prognosis of human breast cancer. J Exp Clin Cancer Res,2005,24(1):75-82.
[14]Lopez JI, et al. CD44 attenuates metastatic invasion during breast cancer progression. Cancer Res,2005,65(15):6755-6763.
[15]Cao G., et al. Involvement of endothelial CD44 during in vivo angiogenesis. Am J Pathol,2006,169(1):325-336.
[16]Bullard RS, et al. Functional analysis of the host defense peptide Human Beta Defensin-1:new insight into its potential role in cancer. Mol Immunol,2008, 45(3):839-848.
[17]Waterman M, et al. Heparanase upregulation by colonic epithelium in inflammatory bowel disease. Mod Pathol,2007,20(1):8-14.
[18]Li RW, et al. Dramatic regulation of heparanase activity and angiogenesis gene expression in synovium from patients with rheumatoid arthritis. Arthritis Rheum,2008,58(6):1590-1600.
[19]Edovitsky E, et al. Role of endothelial heparanase in delayed-type hypersensitivity. Blood,2006,107(9):3609-3616.
[20]Johnson P, Ruffell B. CD44 and its role in inflammation and inflammatory diseases. Inflamm Allergy Drug Targets,2009,8(3):208-220.
[21]Tranter M, Jones WK. Anti-inflammatory effects of HO-1 activity in vascular endothelial cells, commentary on "Carbon monoxide donors or heme oxygenase (HO-1) overexpression blocks interleukin-18-mediated NF-kappaB-PTEN-dependent human cardiac endothelial cell death". Free Radic Biol Med,2008,44(3):261-263.
[1]Yingying X, Yong Z, Zhenning W, et al. Role of heparanase-1 in gastric carcinoma invasion. Asian Pac J Cancer Prev.2009,10(1):151-154.
[2]Malgouries S, Donovan M, Thibaut S, et al. Heparanase 1:a key participant of inner root sheath differentiation program and hair follicle homeostasis. Exp Dermatol.2008,17(12):1017-1023.
[3]Ohtawa Y, Naomoto Y, Shirakawa Y, et al. The close relationship between heparanase and cyclooxygenase-2 expressions in signet-ring cell carcinoma of the stomach. Hum Pathol.2006,37(9):1145-1152.
[4]Fux L, Ilan N, Sanderson RD, et al. Heparanase:busy at the cell surface. Trends Biochem Sci.2009,34(10):511-519.
[5]Tang W, Nakamura Y, Tsujimoto M, et al. Heparanase:a key enzyme in invasion and metastasis of gastric carcinoma. Mod Pathol.2002,15(6):593-598.
[6]刘金禄.乙酰肝素酶的表达调及其与胃癌侵袭转移的关系.中国肿瘤临床.2007,34(11)：657-660.
[7]Dong J, Kukula AK, Toyoshima M, et al. Genomic organization and chromosome localization of the newly identified human heparanasegene. Gene.2000,253(2):
171-178.
[8]Biswas M, Smith JC, Davies JS. Bilateral adrenal enlargement and non-suppressible hypercortisolism as a presenting feature of gastric cancer. Ann Clin Biochem.2004,41(6):494-497.
[9]Nicolson GL, Irimura T, Nakajima M, et al. Metastatic cell attachment to and invasion and vascular endothelium and its underlying basal lamina using endothelial cell monolayers. Symp Fundam Cancer Res.1983,36:145-167.
[10]Takaoka M, Naomoto Y, Ohkawa T, et al. Heparanase expression correlates with invasion and poor prognosis in gastric cancers. Lab Invest.2003,83:613-622.
[11]Inoue H, Mimori K, Utsunomiya T, et al. Heparanase expression in clinical digestive malignancies. Oncol Rep.2001,8(3):539-542.
[12]Xu X, Ding J, Ding H, et al. Immunohistochemical detection of heparanase-1 expression in eutopic and ectopic endometrium from women with endometriosis. Fertil Steril.2007,88(5):1304-1310.
[13]Endo K, Maejara U, Baba H, et al. Heparanase gene expression and metastatic potential in human gastric cancer. Anticancer Res.2001,21(5):3365-3369.
[14]Tang W, Nakamura Y, Tsujimoto M, et al. Heparanase:a key enzyme in invasion and metastasis of gastric carcinoma. Mod Pathol.2002,15(6):593-598.
[15]Shafat I, Zcharia E, Nisman B, et al. An ELISA method for the detection and quantification of human heparanase. Biochem Biophys Res Commun.2006, 341(4):958-963.
[16]Enomoto K, Okamoto H, Numata Y, et al. A simple and rapid assay for heparanase activity using homogeneous time-resolved fluorescence. J Pharm Biomed Anal.2006,41(3):912-917.
[17]Wang Z, Xu H, Jiang L, et al. Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma. Mod Pathol.2005, 18(2):205-211.
[18]Chen JQ, Zhan WH, He YL, et al. Prediction of lymph node metastasis with binary logistic regression in gastric carcinoma. Zhonghua Wei Chang Wai Ke Za Zhi.2005,8(5):436-439.
[19]Wang Z, Zhang X, Xu H, et al. Detection of peritoneal micrometastasis by reverse transcriptase-polymerase chain reaction for heparanase mRNA and cytology in peritoneal wash samples. J Surg Oncol.2005,90(2):59-65.
[20]Ru GQ, Zhao ZS, Tang QL, et al. mRNA expression of syndecan-1 and heparanase in relation to tumor progression and prognosis of gastric carcinoma. Zhonghua Wai Ke Za Zhi.2006,44(15):1062-1064.
[21]刘颖,杨洪钢,左连富.胃癌乙酰肝素酶表达和DNA含量流式细胞定量研究.医学研究杂志.2007,36(10)：40-43.
[22]Cai YG, Fang DC, Yang SM, et al. Increased expression of heparanase mRNA is correlated with metastasis of gastric carcinoma and is probably correlated with c-met protein. Zhonghua Yi Xue Za Zhi.2004,84(12):974-978.
[23]Chen JQ, Zhan WH, He YL, et al. Expression of heparanase gene, CD44v6, MMP-7 and nm23 protein and their relationship with the invasion and metastasis of gastric carcinomas. World J Gastroenterol.2004,10(6):776-782.
[24]刘争,安志强,李恩君,等.乙酰肝素酶、碱性成纤维细胞生长因子在胃癌中表达及对血管新生和肿瘤进展的影响.四川生理科学杂志.2004,26(3)：106-108.
[25]Cao HJ, Fang Y, Zhang X, et al. Tumor metastasis and the reciprocal regulation of heparanase gene expression by nuclear factor kappa B in human gastric carcinoma tissue. World J Gastroenterol.2005,11(6):903-907.
[26]马秀梅,孙勤暖,任明姬,等.胃癌乙酰肝素酶和NF-kB表达及与临床病理特征和血管形成的关系.中国组织化学与细胞化学杂志.2007,16(1)：13-18.
[27]Yingying X, Yong Z, Zhenning W, et al. Role of heparanase-1 in gastric carcinoma invasion. Asian Pac J Cancer Prev.2009,10(1):151-154.
[2]Ou XL, Chen HJ, Sun WH, et al. Effects of angiopoietin-1 on attachment and metastasis of human gastric cancer cell line BGC-823. World J Gastroenterol. 2009,15(43):5432-5441.
[3]Silva M, Azenha D, Pereira C, et al. Gastric carcinoma and chronic gastritis: epigenetic regulation of CDH1 (E-Cadherin), CDKN2A (p16INK4A), PTGS2 (COX-2) and EGFR genes through methylation. Acta Med Port.2010,23(1): 5-14.
[4]Okayama H, Kumamoto K, Saitou K, et al. CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer. Oncol Rep.2009,22(4):745-755.
[5]Ke JJ, Shao QS, Ling ZQ. Expression of E-selectin, integrin betal and immunoglobulin superfamily member in human gastric carcinoma cells and its clinicopathologic significance. World J Gastroenterol.2006,12(22):3609-3611.
[6]Carboni M, Guadagni S, Pistoia MA, et al. Chronic atrophic gastritis and risk of N-nitroso compounds carcinogenesis. Langenbecks Arch Chir.1988,373(2): 82-90.
[7]Stec-Michalska K, Peczek L, Michalski B, et al. Helicobacter pylori infection and family history of gastric cancer decrease expression of FHIT tumor suppressor gene in gastric mucosa of dyspeptic patients. Helicobacter.2009, 14(5):126-134.
[8]Lee KH, Kim JR. Kiss-1 suppresses MMP-9 expression by activating p38 MAP kinase in human stomach cancer. Oncol Res.2009,18(2-3):107-116.
[9]Ohtawa Y, Naomoto Y, Shirakawa Y, et al. The close relationship between heparanase and cyclooxygenase-2 expressions in signet-ring cell carcinoma of the stomach. Hum Pathol.2006,37(9):1145-1152.
[10]Peng L, Ran YL, Hu H, et al. Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway. Carcinogenesis.2009,30(10):1660-1669.
[11]Drebber U, Baldus SE, Nolden B, et al. The overexpression of c-met as a prognostic indicator for gastric carcinoma compared to p53 and p21 nuclear accumulation. Oncol Rep.2008,19(6):1477-1483.
[12]Li YJ, Sun LC, He Y, et al. The anti-tumor properties of two tumstatin peptide fragments in human gastric carcinoma. Acta Pharmacol Sin.2009,30(9): 1307-1315.
[13]Zhao ZS, Wang YY, Ye ZY, et al. Prognostic value of tumor-related molecular expression in gastric carcinoma. Pathol Oncol Res.2009,15(4):589-596.
[14]Gong J, Morishita A, Kurokohchi K, et al. Use of protein array to investigate receptor tyrosine kinases activated in gastric cancer. Int J Oncol.2010,36(1): 101-106.
[15]Besig S, Voland P, Baur DM, et al. Vascular endothelial growth factors, angiogenesis, and survival in human ileal enterochromaffin cell carcinoids. Neuroendocrinology.2009,90(4):402-415.
[16]Malgouries S, Donovan M, Thibaut S, et al. Heparanase 1:a key participant of inner root sheath differentiation program and hair follicle homeostasis. Exp Dermatol.2008,17(12):1017-1023.
[17]Fux L, Ilan N, Sanderson RD, et al. Heparanase:busy at the cell surface. Trends Biochem Sci.2009,34(10):511-519.
[18]Tang W, Nakamura Y, Tsujimoto M, et al. Heparanase:a key enzyme in invasion and metastasis of gastric carcinoma. Mod Pathol.2002,15(6): 593-598.
[19]刘金禄.乙酰肝素酶的表达调及其与胃癌侵袭转移的关系.中国肿瘤临床.2007,34(11)：657-660.
[20]Dong J, Kukula AK, Toyoshima M, et al. Genomic organization and chromosome localization of the newly identified human heparanasegene. Gene. 2000,253(2):171-178.
[21]Ikuta M, Podyma KA, Maruyama K. Expression of heparanase in oral cancer cell lines and oral cancer tissues. Oral Oncol.2001,37 (2):177-184.
[22]徐波,陆茵.乙酰肝素酶促进肿瘤转移分子机制的最新研究进展.安徽医药.2008,12(2)：102-104.
[23]Biswas M, Smith JC, Davies JS. Bilateral adrenal enlargement and non-suppressible hypercortisolism as a presenting feature of gastric cancer. Ann Clin Biochem.2004,41(6):494-497.
[24]Nicolson GL, Irimura T, Nakajima M, et al. Metastatic cell attachment to and invasion and vascular endothelium and its underlying basal lamina using endothelial cell monolayers. Symp Fundam Cancer Res.1983,36:145-167.
[25]Takaoka M, Naomoto Y, Ohkawa T, et al. Heparanase expression correlates with invasion and poor prognosis in gastric cancers. Lab Invest.2003,83: 613-622.
[26]Inoue H, Mimori K, Utsunomiya T, et al. Heparanase expression in clinical digestive malignancies. Oncol Rep.2001,8(3):539-542.
[27]Xu X, Ding J, Ding H, et al. Immunohistochemical detection of heparanase-1 expression in eutopic and ectopic endometrium from women with endometriosis. Fertil Steril.2007,88(5):1304-1310.
[28]Tatro ET, Everall IP, Kaul M, et al. Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: implications for major depressive disorder. Brain Res.2009,1286(25):1-12.
[29]辛晓燕,毛敬,刘玉,等.siRNA抑制卵巢癌细胞株SKOV3 HPSE基因表 达的研究.中国肿瘤生物治疗杂志.2006,13(2)：124-128.
[30]李文才,孙淼淼,张红,等.肝素酶特异性RNAi对人食管癌EC9706细胞肝素酶基因表达的影响.郑州大学学报(医学版).2007,42(1)：9-11.
[31]熊震,汤旭东,房殿春,等.肝素酶RNAi对HepG2肝癌细胞生物学行为的影响.实用临床医药杂志.2008,12(1)：12-16.
[32]王霞,房静远.基因芯片技术在胃黏膜病变中的研究进展.国际消化病杂志.2007,27(3)：188-190.
[1]Yingying X, Yong Z, Zhenning W, et al. Role of heparanase-1 in gastric carcinoma invasion. Asian Pac J Cancer Prev.2009,10(1):151-154.
[2]Ou XL, Chen HJ, Sun WH, et al. Effects of angiopoietin-1 on attachment and metastasis of human gastric cancer cell line BGC-823. World J Gastroenterol. 2009,15(43):5432-5441.
[3]Tatro ET, Everall IP, Kaul M, et al. Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52:implications for major depressive disorder. Brain Res.2009,1286(25):1-12.
[4]Silva M, Azenha D, Pereira C, et al. Gastric carcinoma and chronic gastritis: epigenetic regulation of CDH1 (E-Cadherin), CDKN2A (p16INK4A), PTGS2 (COX-2) and EGFR genes through methylation. Acta Med Port.2010,23(1): 5-14.
[5]Okayama H, Kumamoto K, Saitou K, et al. CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer. Oncol Rep.2009,22(4):745-55.
[6]Ke JJ, Shao QS, Ling ZQ. Expression of E-selectin, integrin betal and immunoglobulin superfamily member in human gastric carcinoma cells and its clinicopathologic significance. World J Gastroenterol.2006,12(22):3609-3611.
[7]Carboni M, Guadagni S, Pistoia MA, et al. Chronic atrophic gastritis and risk of N-nitroso compounds carcinogenesis. Langenbecks Arch Chir.1988,373(2): 82-90.
[8]Stec-Michalska K, Peczek L, Michalski B, et al. Helicobacter pylori infection and family history of gastric cancer decrease expression of FHIT tumor suppressor gene in gastric mucosa of dyspeptic patients. Helicobacter.2009,14(5):126-134.
[9]Lee KH, Kim JR. Kiss-1 suppresses MMP-9 expression by activating p38 MAP kinase in human stomach cancer. Oncol Res.2009,18(2-3):107-116.
[10]Ohtawa Y, Naomoto Y, Shirakawa Y, et al. The close relationship between heparanase and cyclooxygenase-2 expressions in signet-ring cell carcinoma of the stomach. Hum Pathol.2006,37(9):1145-1152.
[11]Zheng LD, Jiang GS, Pu JR, et al. Stable knockdown of heparanase expression in gastric cancer cells in vitro. World J Gastroenterol.2009,15(43):5442-5448.
[12]Friand V, Haddad O, Papy-Garcia D, et al. Glycosaminoglycan mimetics inhibit SDF-1/CXCL12-mediated migration and invasion of human hepatoma cells. Glycobiology.2009,19(12):1511-1524.
[13]Teoh ML, Fitzgerald MP, Oberley LW, et al. Overexpression of extracellular superoxide dismutase attenuates heparanase expression and inhibits breast carcinoma cell growth and invasion. Cancer Res.2009,69(15):6355-6363.
[14]Haupt LM, Murali S, Mun FK, et al. The heparan sulfate proteoglycan (HSPG) glypican-3 mediates commitment of MC3T3-E1 cells toward osteogenesis. J Cell Physiol.2009,220(3):780-791.
[15]Yingying X, Yong Z, Zhenning W, et al. Role of heparanase-1 in gastric carcinoma invasion. Asian Pac J Cancer Prev.2009,10(1):151-154.
[1]Cohen I, et al. Heparanase promotes growth, angiogenesis and survival of primary breast tumors. Int J Cancer,2006,118(7):1609-1617.
[2]Edovitsky E, et al. Heparanase gene silencing, tumor invasiveness, angiogenesis, and metastasis. J Natl Cancer Inst,2004,96(16):1219-1230.
[3]Zcharia E, et al. Transgenic expression of mammalian heparanase uncovers physiological functions of heparan sulfate in tissue morphogenesis, vascularization, and feeding behavior. Faseb J,2004,18(2):252-263.
[4]Zcharia E, et al. Newly generated heparanase knock-out mice unravel co-regulation of heparanase and matrix metalloproteinases. PLoS One,2009, 4(4):5181.
[5]Funa NS, et al. Dysfunctional microvasculature as a consequence of shb gene inactivation causes impaired tumor growth. Cancer Res,2009,69(5): 2141-2148.
[6]Funa NS, et al. Shb gene knockdown increases the susceptibility of SVR endothelial tumor cells to apoptotic stimuli in vitro and in vivo. J Invest Dermatol,2008,128(3):710-716.
[7]Hauck CR, et al. FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. Embo J,2002,21(23): 6289-6302.
[8]Blaschuk OW, Devemy E. Cadherins as novel targets for anti-cancer therapy. Eur J Pharmacol,2009,625(1-3):195-198.
[9]Gory-Faure S, et al. Role of vascular endothelial-cadherin in vascular morphogenesis. Development,1999,126(10):2093-2102.
[10]Liao F, et al. Selective targeting of angiogenic tumor vasculature by vascular endothelial-cadherin antibody inhibits tumor growth without affecting vascular permeability. Cancer Res,2002,62(9):2567-2575.
[11]Ayers M, et al. Discovery and validation of biomarkers that respond to treatment with brivanib alaninate, a small-molecule VEGFR-2/FGFR-1 antagonist. Cancer Res,2007,67(14):6899-6906.
[12]Gotte M, Yip G.W. Heparanase, hyaluronan, and CD44 in cancers:a breast carcinoma perspective. Cancer Res,2006,66(21):10233-10237.
[13]Watanabe O, et al. Expression of a CD44 variant and VEGF-C and the implications for lymphatic metastasis and long-term prognosis of human breast cancer. J Exp Clin Cancer Res,2005,24(1):75-82.
[14]Lopez JI, et al. CD44 attenuates metastatic invasion during breast cancer progression. Cancer Res,2005,65(15):6755-6763.
[15]Cao G., et al. Involvement of endothelial CD44 during in vivo angiogenesis. Am J Pathol,2006,169(1):325-336.
[16]Bullard RS, et al. Functional analysis of the host defense peptide Human Beta Defensin-1:new insight into its potential role in cancer. Mol Immunol,2008, 45(3):839-848.
[17]Waterman M, et al. Heparanase upregulation by colonic epithelium in inflammatory bowel disease. Mod Pathol,2007,20(1):8-14.
[18]Li RW, et al. Dramatic regulation of heparanase activity and angiogenesis gene expression in synovium from patients with rheumatoid arthritis. Arthritis Rheum,2008,58(6):1590-1600.
[19]Edovitsky E, et al. Role of endothelial heparanase in delayed-type hypersensitivity. Blood,2006,107(9):3609-3616.
[20]Johnson P, Ruffell B. CD44 and its role in inflammation and inflammatory diseases. Inflamm Allergy Drug Targets,2009,8(3):208-220.
[21]Tranter M, Jones WK. Anti-inflammatory effects of HO-1 activity in vascular endothelial cells, commentary on "Carbon monoxide donors or heme oxygenase (HO-1) overexpression blocks interleukin-18-mediated NF-kappaB-PTEN-dependent human cardiac endothelial cell death". Free Radic Biol Med,2008,44(3):261-263.
[1]Yingying X, Yong Z, Zhenning W, et al. Role of heparanase-1 in gastric carcinoma invasion. Asian Pac J Cancer Prev.2009,10(1):151-154.
[2]Malgouries S, Donovan M, Thibaut S, et al. Heparanase 1:a key participant of inner root sheath differentiation program and hair follicle homeostasis. Exp Dermatol.2008,17(12):1017-1023.
[3]Ohtawa Y, Naomoto Y, Shirakawa Y, et al. The close relationship between heparanase and cyclooxygenase-2 expressions in signet-ring cell carcinoma of the stomach. Hum Pathol.2006,37(9):1145-1152.
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