Apollon、Smac基因在胃癌中的表达及SPB对胃癌细胞株SGC-7901的抑制研究
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摘要
在诸多的诱导分化剂中,符合高效、低毒在临床上有推广价值的尚少;而苯丁酸钠(sodium phenylbutyrate.SPB)作为一种诱导分化剂,具有对多种肿瘤起作用,毒性反应不大等优点,目前已在美国进入Ⅱ期临床,临床应用前景看好。本实验针对苯丁酸钠对胃癌细胞的增殖抑制、促进分化作用及其机理,进行了胃癌组织和体外细胞培养的实验研究。在细胞水平、亚细胞水平、分子水平进行了流式细胞仪检测、透射电镜观察及半定量RT-PCR检测。
研究中采用免疫组织化学的方法检测胃癌、癌旁和正常胃组织中Apollon蛋白的表达。结果显示Apollon蛋白在胃癌组织中高表达。同时采用RT-PCR的方法检测胃癌组织中Apollon和Smac基因mRNA的表达,并进行相关性分析。结果表明在胃癌组织中,Apollon基因mRNA表达率明显高于癌旁组织和正常组织,Smac基因mRNA在胃癌中的表达弱于癌旁和正常组织,以上均有存在统计学差异。相关分析显示Apollon与Smac的表达呈负相关。
苯丁酸钠可抑制人胃癌SGC-7901细胞生长,呈剂量依赖效应,它可使SGC-7901细胞出现Gl期阻滞,并诱导SGC-7901细胞凋亡,可以更好的抑制人胃癌SGC-7901细胞生长。随着用药浓度增加,Apollon表达明显降低,Smac表达有增高趋势。应用光镜、透射电镜观察到苯丁酸钠作用后胃癌细胞超微结构发生了有意义的形态学变化。通过Dead EndTM比色法TUNEL系统检测不同浓度SPB对SGC-7901细胞原位细胞凋亡,显示用药后细胞凋亡明显。证实SPB对胃癌SGC-7901细胞有较强的抑制作用。
本实验通过对胃组织、以及胃癌细胞株SGC-7901的实验研究,探讨了苯丁酸钠在抑制胃癌发生、发展中的作用,并在不同层面深入研究了Apollon、Smac之间的关系,为进一步研究结胃癌的浸润、转移机制,以及临床胃癌的药物预防、治疗奠定基础。
Human gastric cancer is one of the most common malignant tumor, the incidence of second place in the world. Over the past decadeWith the proto-oncogenes, tumor suppressor gene and the metastasis-associated genes of development in depth, it is recognized that many genetic changes involved in gastric cancer, including oncogene activation, inactivation of tumor suppressor genes and abnormal accumulation of growth factor and its receptor cell adhesion factor and other factors. The occurrence and development involved in a process and results of multi-factor, multi-step, multi-gene.
At present, gastric cancer and precancerous lesions of different stages and different types of pathological changes in molecular biology and had undertaken extensive research. The topic for Apollon, Smac gene in gastric cancer specimens and cancer cell lines SGC-7901 cells were studied. Through the experimental study, we provide the new content of the occurrence of the tumor and the development of mechanisms. It is possible one kinds of new tumor markers and cancer treatment is expected to make it on a new target for the diagnosis and prognosis of tumor.
Through the experimental sodium phenylbutyrate inhibited on human gastric cancer cell line SGC-7901. On the cellular level and sub-cellular level through the cell proliferation inhibition rate detection, flow cytometry, electron microscopy and RT-PCR detection, a preliminary conclusion that sodium phenylbutyrate inhibit on human gastric cancer SGC-7901 cell is confirmed. Apollon, Smac gene in gastric cancer cells expressed Separatly, suggesting that the Apollon, Smac gene may be related to the occurrence of malignant tumors.
1.Experiment through the immunohistochemical method detect of the expression levels of Apollon.Results showed that: Apollon protein highly expressed in gastric cancer contrast to normal gastric tissue in the low-expression and the result exist of significant difference (p <0.05). Apollon protein expression unrelated to sex, age, incidence of the site. There is no significant difference between results (p> 0.05). Apollon protein expression relate to pathological staging and grading of gastric cancer .It unrelate to tumor size. In addition, Apollon protein expression in gastric cancer tissue relate to the degree of differentiation. Apollon protein expression higher in well-differentiated and undifferentiated relatively low and it has statistical significance (p <0.05). Apollon protein expression in the same relate to clinical stage.Lymph node metastasis may be nothing to do with and no significant difference exist between the two (p>0.05).
2.Through the experimental method of RT-PCR we detect of Apollon, Smac gene in gastric cancer cases. Apollon mRNA in gastric cancer was highly expressed and it was significantly higher than adjacent tissues and normal gastric tissue (p <0.05). Apollon gene expression has nothing to do with the size of tumor (P> 0.05). With tumor differentiation, there is statistical significance in phases (P <0.05). It May be nothing to do with the lymph node metastasis. Smac gene in gastric cancer with low expression was significantly lower than adjacent tissues and normal gastric tissue (p <0.05), so we conclude the low expression of Smac gene relate to the occurrence of gastric cancer. Smac gene expression has nothing to do with the size of tumor (P> 0.05). With tumor type, differentiation degree, there is statistical significance (P <0.05). Tumor stage is worse when Smac is lower expression. However it is no statistical significance (p> 0.05). Lymph node metastasis relate to expression of Smac( P<0.05). The relation of expression of both Apollon and Smac gene are negatively correlated and Apollon high expression contrast to low expression of Smac in tumor.
3. In this experiment through the MTT colorimetric assay ,we detect that sodium phenylbutyrate inhibit on human gastric cancer SGC-7901 cell proliferation. The results showed that with the dosage of sodium phenylbutyrate, gastric cancer cell inhibitory rate increased; With the use of extended time, the inhibitory rate of gastric cancer has also increased, showing time and dose-dependent manner. Through flow cytometry we found that sodium phenylbutyrate can make gastric cancer SGC-7901 cell block in the G0/G1 phase, so the proportion of G0/G1 phase cells increased. Through inverted microscope we observe cell morphology, negative control group of adherent growth SGC-7901 cells were polygonal. Uniform cell size, vigorous growth. After sodium phenylbutyrate role in cells, a relatively slow cell growth, cell expansion as well as the gap between the decrease in the number of cells showed significant cell growth inhibition. At the same time, cell morphology can be seen from the cobblestone into fibroblast-like cells similar to spindle shape.With increased drug concentration and the role of time, the change is obviousl. Under the electron microscope observation of SGC-7901 cells (control group, cells without drugs) were polymorphic, cell structure integrity, cell-developed, often very structured nuclear shape and nuclear-mass ratio increased significantly. SPB4.0mM apply for 72 hours after the SGC-7901 cells in the first days after 1,2,3, synaptic nuclei were round to reduce the nuclear and nuclear-mass ratio decreased and mitochondrial swell and cristae disappear .In cytoplasmic lipid droplets in the number of the increase in varying degrees, part of a large number of intracellular lipid droplets, lipid droplets of lipid for the synthesis of gastric epithelial cells to form lipid bodies in the electron microscope.The cytoplasm showed vacuolization body.This shows that benzene sodium butyrate inhibit the SGC-7901 cell.
4. Colorimetric TUNEL System Dead EndTM detect different concentrations of SGC-7901 cell apoptosis in situ by sPB. Through optical microscope we observed cells stained and randomly selected 10 vision counting the number of positive cells. Observation results show that positive cells is not found in the control group in the field of vision, and in each group of drug positive cells can be seen, and with the increase in drug concentration, the number of positive cells increase. The results suggest that: sodium phenylbutyrate inhibit on growth of human gastric cancer cell.This experiment also confirmed that Apollon gene in gastric cancer cell lines express positively and its expression weaken when sodium phenylbutyrate role in human gastric cancer cell line.Smac gene exit in human gastric cancer cell line and express negatively, and With the sodium phenylbutyrate on human gastric cancer cell line Smac increased its expression and its expression changes relate to sodium phenylbutyrate on the end of the inhibition mechanism of gastric cancer.
研究中采用免疫组织化学的方法检测胃癌、癌旁和正常胃组织中Apollon蛋白的表达。结果显示Apollon蛋白在胃癌组织中高表达。同时采用RT-PCR的方法检测胃癌组织中Apollon和Smac基因mRNA的表达,并进行相关性分析。结果表明在胃癌组织中,Apollon基因mRNA表达率明显高于癌旁组织和正常组织,Smac基因mRNA在胃癌中的表达弱于癌旁和正常组织,以上均有存在统计学差异。相关分析显示Apollon与Smac的表达呈负相关。
苯丁酸钠可抑制人胃癌SGC-7901细胞生长,呈剂量依赖效应,它可使SGC-7901细胞出现Gl期阻滞,并诱导SGC-7901细胞凋亡,可以更好的抑制人胃癌SGC-7901细胞生长。随着用药浓度增加,Apollon表达明显降低,Smac表达有增高趋势。应用光镜、透射电镜观察到苯丁酸钠作用后胃癌细胞超微结构发生了有意义的形态学变化。通过Dead EndTM比色法TUNEL系统检测不同浓度SPB对SGC-7901细胞原位细胞凋亡,显示用药后细胞凋亡明显。证实SPB对胃癌SGC-7901细胞有较强的抑制作用。
本实验通过对胃组织、以及胃癌细胞株SGC-7901的实验研究,探讨了苯丁酸钠在抑制胃癌发生、发展中的作用,并在不同层面深入研究了Apollon、Smac之间的关系,为进一步研究结胃癌的浸润、转移机制,以及临床胃癌的药物预防、治疗奠定基础。
Human gastric cancer is one of the most common malignant tumor, the incidence of second place in the world. Over the past decadeWith the proto-oncogenes, tumor suppressor gene and the metastasis-associated genes of development in depth, it is recognized that many genetic changes involved in gastric cancer, including oncogene activation, inactivation of tumor suppressor genes and abnormal accumulation of growth factor and its receptor cell adhesion factor and other factors. The occurrence and development involved in a process and results of multi-factor, multi-step, multi-gene.
At present, gastric cancer and precancerous lesions of different stages and different types of pathological changes in molecular biology and had undertaken extensive research. The topic for Apollon, Smac gene in gastric cancer specimens and cancer cell lines SGC-7901 cells were studied. Through the experimental study, we provide the new content of the occurrence of the tumor and the development of mechanisms. It is possible one kinds of new tumor markers and cancer treatment is expected to make it on a new target for the diagnosis and prognosis of tumor.
Through the experimental sodium phenylbutyrate inhibited on human gastric cancer cell line SGC-7901. On the cellular level and sub-cellular level through the cell proliferation inhibition rate detection, flow cytometry, electron microscopy and RT-PCR detection, a preliminary conclusion that sodium phenylbutyrate inhibit on human gastric cancer SGC-7901 cell is confirmed. Apollon, Smac gene in gastric cancer cells expressed Separatly, suggesting that the Apollon, Smac gene may be related to the occurrence of malignant tumors.
1.Experiment through the immunohistochemical method detect of the expression levels of Apollon.Results showed that: Apollon protein highly expressed in gastric cancer contrast to normal gastric tissue in the low-expression and the result exist of significant difference (p <0.05). Apollon protein expression unrelated to sex, age, incidence of the site. There is no significant difference between results (p> 0.05). Apollon protein expression relate to pathological staging and grading of gastric cancer .It unrelate to tumor size. In addition, Apollon protein expression in gastric cancer tissue relate to the degree of differentiation. Apollon protein expression higher in well-differentiated and undifferentiated relatively low and it has statistical significance (p <0.05). Apollon protein expression in the same relate to clinical stage.Lymph node metastasis may be nothing to do with and no significant difference exist between the two (p>0.05).
2.Through the experimental method of RT-PCR we detect of Apollon, Smac gene in gastric cancer cases. Apollon mRNA in gastric cancer was highly expressed and it was significantly higher than adjacent tissues and normal gastric tissue (p <0.05). Apollon gene expression has nothing to do with the size of tumor (P> 0.05). With tumor differentiation, there is statistical significance in phases (P <0.05). It May be nothing to do with the lymph node metastasis. Smac gene in gastric cancer with low expression was significantly lower than adjacent tissues and normal gastric tissue (p <0.05), so we conclude the low expression of Smac gene relate to the occurrence of gastric cancer. Smac gene expression has nothing to do with the size of tumor (P> 0.05). With tumor type, differentiation degree, there is statistical significance (P <0.05). Tumor stage is worse when Smac is lower expression. However it is no statistical significance (p> 0.05). Lymph node metastasis relate to expression of Smac( P<0.05). The relation of expression of both Apollon and Smac gene are negatively correlated and Apollon high expression contrast to low expression of Smac in tumor.
3. In this experiment through the MTT colorimetric assay ,we detect that sodium phenylbutyrate inhibit on human gastric cancer SGC-7901 cell proliferation. The results showed that with the dosage of sodium phenylbutyrate, gastric cancer cell inhibitory rate increased; With the use of extended time, the inhibitory rate of gastric cancer has also increased, showing time and dose-dependent manner. Through flow cytometry we found that sodium phenylbutyrate can make gastric cancer SGC-7901 cell block in the G0/G1 phase, so the proportion of G0/G1 phase cells increased. Through inverted microscope we observe cell morphology, negative control group of adherent growth SGC-7901 cells were polygonal. Uniform cell size, vigorous growth. After sodium phenylbutyrate role in cells, a relatively slow cell growth, cell expansion as well as the gap between the decrease in the number of cells showed significant cell growth inhibition. At the same time, cell morphology can be seen from the cobblestone into fibroblast-like cells similar to spindle shape.With increased drug concentration and the role of time, the change is obviousl. Under the electron microscope observation of SGC-7901 cells (control group, cells without drugs) were polymorphic, cell structure integrity, cell-developed, often very structured nuclear shape and nuclear-mass ratio increased significantly. SPB4.0mM apply for 72 hours after the SGC-7901 cells in the first days after 1,2,3, synaptic nuclei were round to reduce the nuclear and nuclear-mass ratio decreased and mitochondrial swell and cristae disappear .In cytoplasmic lipid droplets in the number of the increase in varying degrees, part of a large number of intracellular lipid droplets, lipid droplets of lipid for the synthesis of gastric epithelial cells to form lipid bodies in the electron microscope.The cytoplasm showed vacuolization body.This shows that benzene sodium butyrate inhibit the SGC-7901 cell.
4. Colorimetric TUNEL System Dead EndTM detect different concentrations of SGC-7901 cell apoptosis in situ by sPB. Through optical microscope we observed cells stained and randomly selected 10 vision counting the number of positive cells. Observation results show that positive cells is not found in the control group in the field of vision, and in each group of drug positive cells can be seen, and with the increase in drug concentration, the number of positive cells increase. The results suggest that: sodium phenylbutyrate inhibit on growth of human gastric cancer cell.This experiment also confirmed that Apollon gene in gastric cancer cell lines express positively and its expression weaken when sodium phenylbutyrate role in human gastric cancer cell line.Smac gene exit in human gastric cancer cell line and express negatively, and With the sodium phenylbutyrate on human gastric cancer cell line Smac increased its expression and its expression changes relate to sodium phenylbutyrate on the end of the inhibition mechanism of gastric cancer.
引文
[1]陈孝平.外科相关的基础医学科学.外科学,人民卫生出版社,2007,16-20.
[2]Varmus H E.The molecular genetics of cellular oncogenes.Ann Rev Genet, 1984;18:553.
[3]Bishop J M.The molecular genetics of cancer.Science,1987;235:305.
[4]Kong-Beltran M, Stamos J, Wickramasinghe D. The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell, 2004,6:75-84.
[5]Longati P, Bardelli A, Ponzetto C, et al. Tyrosines1234- 1235 are critical for activation of the tyrosine kinase encoded by the MET proto- oncogene (HGF receptor). Oncogene, 1994,9:49-57.
[6]Ponzetto C, Bardelli A, Zhen Z, et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell, 1994,77:261-271.
[7]庄小强,郑杰,林三仁,等. c- Met蛋白表达与胃黏膜病变的关系及预后意义.中华病理学杂志, 2000,29:409-411.
[8]Tsujimoto Y,Croce CM.Analysis of the structure,transcripts,and protein products of bcl-2,the gene involed in human follicular lymphoma.Proc Natl Acad Sci USA,1986,83(12):5214-5217.
[9]Korsmeyer SJ.Bcl-2 initiates a new category of oncogenes regulators of cell death.Blood,1992,80:897.
[10]Cory S,Huang DC,Adam JM.The Bcl-2 family:roles in cell survival and oncogenesis.Oncogene,2003,24(8):859.
[11]刘福坤,许哲.全胃切除术后的营养障碍与防治[J].中国实用外科杂志,1997, 17: 715-716.
[12]Hang L ,Be W,Mary L,et al.EGFR and C-erbB2 differentially regulate Ral-1 translocation and activation[J].Lab Invest,2002 ,82(1) :71-78.
[13]Bal MM ,Das Radotra B ,Srinivasan R ,et al.Does c-erbB2 expression have a role in medulloblastoma prognosis[J] .Indian J Pathol Microbiol ,2006 ,49(4):535-539.
[14]Vizoso FJ, Corte MD.et al. Membranous levels of c-erbB-2 oncoprotein in gastric cancer: their relationship with clinicopathological parameters and their prognostic significance. Int J Biol Markers. 2004 Oct-Dec;19(4):268-74
[15]Lee SW, Kang SB.et al. Expression of c-erbB-2 and c-met proteins in gastric adenoma and adenocarcinoma. Korean J Gastroenterol. 2007 Mar;49(3):152-7.
[16]Wang DX,Fang DC,Liu WW.Induction of intestinal metaplasia in stomach of dogs and expression of tumor-related proteins in animal gastric mucosa lesions. Chin Med J,2000,113(1):336-341.
[17]Rask K,Nillson A,Bannstrom M,et al.Wnt-signalling pathway in ovarian epithelial tumors:increased expression ofβ-catenin and GSK-3β.BrJ Cancer,2003, 89(7):298-304.
[18]Park WS,Oh RR,Park JY,et al.Frequent somatic mutations of theβ-catenin gene in intestinal-type gastric cancer.Cancer Res,1999,59 (5):4257-4260.
[19]Field JK.The role of oncogenes and tumor-suppressor genes in the aetiology of oral,head and neck squamous cell carcinoma.J R Soc Med,1995,88(1): 35.
[20]Nakamura T,Pichel JG,Siaons LW,etal.An apoptotic defect in lens differ- entiation caused by human p53 is rescued by amutant allele.Proc Natl Acad USA,1995,92:6142.
[21]Koorey DJ,McCaughan GW,Trent RJ,et al.Exon eight APC mutations account for a disproportionate number of familial adenomatous polyposis families.Hum Mutat,1994,3(1):12-18.
[22]:Grace A, Butler D.et al. APC gene expression in gastric carcinoma: an immunohistochemical study. Appl Immunohistochem Mol Morphol. 2002 Sep;10(3):221-4.
[23] Wang D, Fang D.et al. Study of loss of heterozygosity at DCC and APC/MCC genetic loci of gastric cancer. Chin Med Sci J. 1999 Jun;14(2):107-11.
[24]Sato K, Tamura G, Frequent loss of expression without sequence mutations of the DCC gene in primary gastric cancer. Br J Cancer. 2001 Jul 20;85(2):199-203.
[25]Steele RJC, Thompson AM ,Hall PA ,et al.The p53 tumour suppressor gene[J] . British Journal of Surgery,1998,85 :1460-1467.
[26]Levine AJ , Momand J ,Finlay CA ,et al. The p53 tumour suppressor gene[J ] . Nature,1991 ,315 :453.
[27]Ichikawa A , Hotta T , Takagi N , et al. Mutations of p53 gene and their relation to disease progression in B-cell lymphoma[J]. Blood, 1992 , 79(10) :2701-2707.
[28] M?nig SP, Nolden B.etal. Clinical significance of nm23 gene expression in gastric cancer. 2007 Jul-Aug;27(4C):3029-33.
[29] Wang LB, Jiang ZN. Changes of histology and expression of MMP-2 and nm23-H1 in primary and metastatic gastric cancer. World J Gastroenterol. 2008 Mar 14;14(10):1612-6.
[30]Nomura H,Fujimoto N,Seiki M,et al.Enhanced production of matrix metalloproteinases and activation of matrix metalloproteinase 2 (gelatinase A)in human gastric carcinomas.Int J Cancer.1996 Feb 20; 69(1):9-16.
[31]Heider KH, Dammrich J, Skroch-Angel P, et al. Differential expression of CD44 variants intestinal and diffuse-type human gastric carcinomas and normal gastric mucosa [J]. Cancer Res, 1993, 53(8):4197 - 4203.
[32]Ham HJ, Ho LT, Chang JY, et al. Differential expression of the human metastasis adhesion molecule CD44v in normal and carcinomatous stomach mucosa of Chinese subjects[ J ]. Cancer, 1995, 75 (4):1065-1071.
[33]Mirecka J,Mark D, Schauer A,et al. Immunohistochemical localization of CD44 variants 5 and 6 in human gastric mucosa and gastric.
[34]Mayer B, Jauch KW, Gunthert U, et al. De-novo expression of CD44 and survival in gastric cancer [J].Lancet,1993,342 (8):1019 -1022.
[35]Hong RL,Lee WJ, Shun CT,et al.Expression of CD44 and its clinical implication in diffuse-type and intestinal-type gastrica denocarcinoma [J]. Oncology, 1995, 52 (4):334.
[36]Wu CY, Wu MS.et al. Clinicopathological significance of urokinase-type plasminogen activator genotypes in gastric cancer. Hepatogastroenterology. 2008 Sep-Oct;55(86-87):1890-4.
[37]Zhang FH, Zhou YN.et al. Expression of cyclooxygenase-2 and urokinase plasminogen activator in gastric carcinoma and the clinical significance. Zhonghua Yi Xue Za Zhi. 2008 Dec 16;88(46):3279-82
[38]Liu WT, Jiao HL.et al. Correlation of E-cadherin hypermethylation to tumorigenesis and development of gastric cancer. Ai Zheng. 2007 Nov;26(11):1199-203
[39]王东旭,房殿春,周晓东,等.胃癌组织5q微卫星不稳定性与APC/MCC基因杂合性缺失的研究.中华消化杂志,1999,19(2):107-110.
[40]Rhyu MG,Park WS,Jung YL,etal.Allelic deletions of MCC/APC and p53 are frequent late events in human gastric carcinogenesis. Gastroenterology, 1994,106: 1584-1587.
[41]Stricler JG,Zheng J,Shu Q,etal.p53 mutations and microsatellate instability in sporadic gastric cancer:when guardians fail.Cancer Res, 1994,54:4750-4755.
[42]Mironor NM,Aguelon AM,Potapovn GI,etal.Alterations of(CA)DNA repeats and tumor suppressor genes in human gastric cancer.Cancer Res,1994,54:41-44.
[43]Wang W,Luo HS,Yu BP.Telomerase and colorectal cancer.Shijie Huaren Xiaohua Zazhi,2000,8:800.
[44]唐发清,蒋海鹰,段朝军,等.鼻咽上皮癌变过程中端粒酶活性和端粒酶RNA的表达.中华病理学杂志,2001,30:125.
[45]Kim NW,Hruszkewycz AM.Telomerase activity modulation in theprevention of prostate cancer.Urology,2001,57(4Suppl1):148.
[46]LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Bairdand S, Korneluk RG. IAP-targeted therapies for cancer. Oncogene. 2008;27:6252–6275.
[47]Vucic D, Fairbrother WJ. The Inhibitor of Apoptosis Proteins as Therapeutic Targets in Cancer. Clin Cancer Res. 2007;13:5995–6000.
[48] Eckelman BP, Salvesen SG, Scott FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006;7:988–994.
[49] Vucic D, Fairbrother WJ. The Inhibitor of Apoptosis Proteins as Therapeutic Targets in Cancer. Clin Cancer Res. 2007;13:5995–6000.
[50]SongZ,YaoX,WuM.Directinteraction between survivin and Smac is essential for the antiapoptoticactivity of survivin during Taxol-induced apoptosis. J Biol Chem ,2003; 278 (25) :23130～40.
[51]Richter BW,Mir SS,Eiben LJ et al .Molecularclonin gofILP-2,A novel member of the inhibitor of apoptosis protein family. Mol Cell Biol ,2001; 21 (13) :4292～301.
[52]Eckelman BP, Salvesen SG, Scott FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006;7:988–994.
[53]Fulda S. Inhibitor of apoptosis proteins in hematological malignancies. Leukemia. 2009;23:467–76.
[54]Fotin-MleczekM, HenklerF,SamelD et al .A poptoticcrosstalk of TNF receptors:TNF-R-2 induces depletion of TRAF2 and IAP Proteins and accelerates TNF-R1-dependent activation of caspase-8. J Cell Sci ,2002; 115 ( Pt13 ) :2757～70.
[55]Sanna MG,daSilvaCorreiaJ,Ducrey OM et al .IAP suppression of apoptosis involves distinct mechanisms:the TAK1/JNK1 signaling cascade and caspase inhibition. Mol Cell Biol , 2002; 22 (6) :1754～66.
[56]Suga K, Yamamoto T, Yamada Y, et a.l Correlation between transcripti- onalexpression ofsurvivin isoforms and clinicopathological findings in human colorectal carcinomas [J]. OncolRep, 2005, 13: 891-897.
[57]McElenyKR, Watson RW, Coffey RN, et a.l Inhibitors of apoptosis proteins in prostate cancer cell lines [J].Prostate, 2002, 51: 133-140.
[58]Liu J, LiM, Xia S. Expression and clinical significance of antiapoptosis gene XIAP in prostate cancer [J]. Natl J Androl (中华男科), 2004, 10: 832-835.
[59]Jang JY, Kim HJ, Chi SG, et al. Frequent epigenetic inactivation of XAF1 by promotor hypermethylation in human colon cancers [J]. Korean JGastroentero,l2005,45: 285-293.
[60]MaTL, NiPH, Zhong J, etal. Low expression of XIAP-associated factor1 in human colorectal cancers [J]. Chin J Dig Dis, 2005,6:10-14.
[61]Roy N, Mahadevan MS, McLean M, et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. J.Cell, 1995, 80 (1) : 167～178.
[62] Xu D.G. et al. (1997a) Elevation of neuronal expression of NAIP reduces ischemic damage in the rat hippocampus. Nature Med., 3:, 997–1004.
[63]u D.G., Korneluk,R.G., Tamai,K., Wigle,N., Hakim,A., Mackenzie,A. and Robertson,G.S. (1997b) Distribution of neuronal apoptosis inhibitory protein-like immunoreactivity in the rat central nervous system. J. Comp. Neurol., 382:, 247–259.
[64]Abe s,Yamamoto K,Hasegawa M,et al.Bone marrow cells of myelodysplastic syndromes exhibit singnificat expression of apollion,livin and ILP-2 with reduction after transformation to overt leukemia.Leuk Res.2005 S,29(9):1095-6.
[65]孙鹏. AF1q基因、ILP-2与Smac在白血病中的表达及意义.[D].中国优秀硕士学位论文全文数据库,2007,(11).
[66]Yonesaka K, Tamura K, Kurata T, et a.l Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to adriamycin [J]. Int J Cancer,2005, in press.
[67]Hu Y, Cherton-HorvatG, DragowskaV, eta.l Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo[J]. Clin CancerRes,2003,9: 2826-2836.
[68]Carter BZ, Milella M, Tsao T, et al. Regulation and targeting of antiapoptotic XIAP in acutemyeloid leukemia[J]. Leukemia, 2003, 17: 2081-2089.
[69]Bilim V, Kasahara T, Hara N, et al. Role of XIAP in The malignant phenotype of transitional cell cancer(TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistant TCC in vitro[J]. Int J Cancer, 2003, 103: 29-37.
[70]Crnkovic-Mertens I, Hoppe-Seyler F, Butz K. Induction o fapoptosis intumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene [J]. Oncogene, 2003, 22:8330-8336.
[71]McEleny K, Coffey R, Morrissey C, et al. An antisense oligonucleotide to cIAP-1 sensitizes prostate cancer cells to fas and TNF alpha mediated apoptosis [J]. Prostate,2004, 59: 419-425.
[72]Wang XW, Fu LW. Inhibator of apoptosis proteins (IAP): new target of anticancer [J]. Chin Pharmacol Bull (中国药理学通报), 2004, 20: 129-133.
[73]Yang L, Mashima T, Sato S, et al. Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: therapeutic effect of a novel polyarginine-conjugated Smac peptide [J]. CancerRes, 2003, 63: 831-837.
[74]Sekine K, Hao Y, Suzuki Y, et al. HtrA2 cleaves Apollon and induces cell death by IAP-binding motif in Apollon-deficient cells [J]. Biochem Biophys Res Commun, 2005, 330: 279-285.
[75]anahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.
[76]aux DL, Korsmeyer SJ. Cell death in development. Cell. 1999;96(2):245–254.
[77]van Loo G, Saelens X, van Gurp M, MacFarlane M, Martin SJ, Vandenabeele P. The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. Cell Death Differ. 2002;9(10):1031–1042.
[78]Zou H, Li Y, Liu X, Wang X. An APAF-1. cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem. 1999;274(17):11549–11556.
[79]Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell. 1998;94(3):325–337.
[80] DU C , Fang M,Li Y,et al . Smac ,a mitochondrial protein that promotes Cytochrome-dependent caspase activation by elimination IAP inhibition [J]. Cell, 2000, 102(1) :33.
[81]Srinivasa MS ,Datta P ,Xun JU ,et al . Molecular determinants of thecaspase-promoting activity of Smac/ DIABLO and its role in the death receptor pathway[J] .Biol Chem ,2000 ,275 :36152.
[82]u C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102(1):33–42.
[83]hai J, Du C, Wu JW, Kyin S, Wang X, Shi Y. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature. 2000;406(6798):855–862.
[84]Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y. Structural basis of IAP recognition by Smac/DIABLO. Nature. 2000;408(6815):1008–1012.
[85]Srinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J, Lee RA, Robbins PD, Fernandes-Alnemri T, Shi Y, et al. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature. 2001;410(6824):112–116.
[86]Kashkar H, Haefs C, Shin H, Hamilton-Dutoit SJ, Salvesen GS, Kronke M, Jurgensmeier JM. XIAP-mediated caspase inhibition in Hodgkin's lymphoma-derived B cells. J Exp Med. 2003;198(2):341–347.
[87]Arnt CR, Chiorean MV, Heldebrant MP, Gores GJ, Kaufmann SH. Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ. J Biol Chem. 2002;277(46):44236–44243.
[88]Mizukawa K, Kawamura A, Sasayama T, Tanaka K, Kamei M, Sasaki M, Kohmura E. Synthetic Smac peptide enhances the effect of etoposide-induced apoptosis in human glioblastoma cell lines. J Neurooncol. 2006;77(3):247–255.
[89]Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG. A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science. 2004;305(5689):1471–1474.
[90]Bockbrader KM, Tan M, Sun Y. A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells. Oncogene. 2005;24(49):7381–7388.
[91]Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, et al. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell. 2007;131(4):682–693.
[92]Fulda S, Wick W, Weller M, Debatin KM. Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med. 2002;8(8):808–815.
[93]Zhao J, Jin J, Zhang X, Shi M, Dai J, Wu M, Wang R, Guo Y. Transfection of Smac sensitizes tumor cells to etoposide-induced apoptosis and eradicates established human hepatoma in vivo. Cancer Gene Ther. 2006;13(4):420–427.
[94]Yan Y, Mahotka C, Heikaus S, Shibata T, Wethkamp N, Liebmann J, Suschek CV, Guo Y, Gabbert HE, Gerharz CD, et al. Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas. Br J Cancer. 2004;91(7):1349–1357.
[95]Kempkensteffen C, Hinz S, Christoph F, Krause H, Magheli A, Schrader M, Schostak M, Miller K, Weikert S. Expression levels of the mitochondrial IAP antagonists Smac/DIABLO and Omi/HtrA2 in clear-cell renal cell carcinomas and their prognostic value. J Cancer Res Clin Oncol. 2008;134(5):543–550.
[96]Mizutani Y, Nakanishi H, Yamamoto K, Li YN, Matsubara H, Mikami K, Okihara K, Kawauchi A, Bonavida B, Miki T. Downregulation of Smac/DIABLO expression in renal cell carcinoma and its prognostic significance. J Clin Oncol. 2005;23(3):448–454.
[97]Hofmann HS, Simm A, Hammer A, Silber RE, Bartling B. Expression of inhibitors of apoptosis (IAP) proteins in non-small cell human lung cancer. J Cancer Res Clin Oncol. 2002;128(10):554–560.
[98]Hu Y, Cherton-Horvat G, Dragowska V, Baird S, Korneluk RG, Durkin JP, Mayer LD, LaCasse EC. Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo. Clin Cancer Res. 2003;9(7):2826–2836.
[99]Bao ST, Gui SQ, Lin MS. Relationship between expression of Smac and Survivin and apoptosis of primary hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2006;5(4):580–583.
[100]Espinosa M, Cantu D, Lopez CM, De la Garza JG, Maldonado VA, Melendez-Zajgla J. SMAC is expressed de novo in a subset of cervical cancer tumors. BMC Cancer. 2004;4:84.
[101]Arellano-Llamas A, Garcia FJ, Perez D, Cantu D, Espinosa M, De la Garza JG, Maldonado V, Melendez-Zajgla J. High Smac/DIABLO expression is associated with early local recurrence of cervical cancer. BMC Cancer. 2006;6:256.
[102]Shibata T, Mahotka C, Wethkamp N, Heikaus S, Gabbert HE, Ramp U. Disturbed expression of the apoptosis regulators XIAP, XAF1, and Smac/DIABLO in gastric adenocarcinomas. Diagn Mol Pathol. 2007;16(1):1–8.
[103]Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG. Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol. 2001;3(2):128–133.
[104]Yang L,Mashima T ,Sato S,et al. Predominant Suppression of Apoptosome by Inhibitor of Apoptosis Protern in Non-small Cell Lung Cancer H460 Cells: Therapeutic Effect of a Novel Polyarginine-conjugated Smac Peptide.Cancer Res,2003,63(4):831-837.
[105]Nagamine M, Okumura T, Tanno S,et al. PPAR gamma ligand-induced apoptosis through a p53-dependent mechanism in human gastric cancer ce1ls.Cancer Sci.2003;94(4):338-343.
[106]Baek SJ, Wilson LC, His LC,etal.Troglitazone,a peroxisome proliferator-activated receptor gamma (PPAR gamma)ligand, selectively induces the early growth response-1 gene independently of PPAR gamma. A novel mechanism for its anti-tumorigenic activity.J Biol Chem. 2003;278(8):5845-5853.
[107]Strakova N, Ehrmann J, Dzubak P,et al. The synthetic ligand of peroxisome proliferator-activated receptor-gamma ciglitazone affects human glioblastoma celllines.Pharmacol Exp Ther. 2004;309(3):1239-1247.
[108]Han S, Sidell N, Fisher PB, et al. Up-regulation of p21 gene expressionby peroxisome proliferator-activated receptor gamma in human lung carcinoma cells.Clin Cancer Res.2004;10(6):1911一1919.
[109]Koga H, Sakisaka S, Harada M, et al.Involvement of p21(WAF1/Cip1), p27(Kipl), and p18(INK4c) in troglitazone-induced cell-cycle arrest in human hepatoma cell lines.Hepatology. 2001;33(5):1087-1097.
[110]潘华锋,陈孝平.Ciglitazone抑制人肝癌HepG2细胞增殖活性的实验研究[J].中华实验外科杂志,2004,21(8):934-936.
[111]孙象军.苯丁酸钠及二甲基甲酰胺对乳腺癌细胞增殖抑制及诱导分化的实验研究.[D].中国优秀博学位论文全文数据库,2007,(11).
[112]Samid D,Hudgins WR,Shack S,et al.Phenylacetate and phenylbutyrate as novel,nontoxic differentiation inducers[J].Adv Exp Med Biol.1997,400:501-505.
[113] Baker MJ, Brem S,etal. Complete response of a recurrent, multicentric malignant glioma in a patient treated with phenylbutyrateJ Neurooncol. 2002 Sep;59(3):239-42.
[114] Calvaruso G, CarabillòM,et al. Sodium phenylbutyrate induces apoptosis in human retinoblastoma Y79 cells: the effect of combined treatment with the topoisomerase I-inhibitor topotecan. Int J Oncol. 2001 Jun;18(6):1233-7.
[115]Yu KH,Weng LJ,Fu S,et al.Augmentation of phenylbutyrate-induced differentiation of myeloid leukemia cells using all-trans retinoid acid[J]. Leukemia, 1999,13:1258-1265.
[116] Gore SD, Samid D, Weng LJ. Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells. Clin Cancer Res. 1997 Oct;3(10):1755-62
[117] Meng M, Jiang JM, Liu H,et al. Effects of sodium phenylbutyrate on differentiation and induction of the P21WAF1/CIP1 anti-oncogene in human liver carcinoma cell lines.Chin J Dig Dis. 2005;6(4):189-92.
[118] Gao J, Ruan X,etal. The effect of sodium phenylbutyrate to agents used in induction chemotherapy on laryngeal carcinoma cells Hep-2 in vitro.Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2005 Aug;19(15):680-2.
[2]Varmus H E.The molecular genetics of cellular oncogenes.Ann Rev Genet, 1984;18:553.
[3]Bishop J M.The molecular genetics of cancer.Science,1987;235:305.
[4]Kong-Beltran M, Stamos J, Wickramasinghe D. The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell, 2004,6:75-84.
[5]Longati P, Bardelli A, Ponzetto C, et al. Tyrosines1234- 1235 are critical for activation of the tyrosine kinase encoded by the MET proto- oncogene (HGF receptor). Oncogene, 1994,9:49-57.
[6]Ponzetto C, Bardelli A, Zhen Z, et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell, 1994,77:261-271.
[7]庄小强,郑杰,林三仁,等. c- Met蛋白表达与胃黏膜病变的关系及预后意义.中华病理学杂志, 2000,29:409-411.
[8]Tsujimoto Y,Croce CM.Analysis of the structure,transcripts,and protein products of bcl-2,the gene involed in human follicular lymphoma.Proc Natl Acad Sci USA,1986,83(12):5214-5217.
[9]Korsmeyer SJ.Bcl-2 initiates a new category of oncogenes regulators of cell death.Blood,1992,80:897.
[10]Cory S,Huang DC,Adam JM.The Bcl-2 family:roles in cell survival and oncogenesis.Oncogene,2003,24(8):859.
[11]刘福坤,许哲.全胃切除术后的营养障碍与防治[J].中国实用外科杂志,1997, 17: 715-716.
[12]Hang L ,Be W,Mary L,et al.EGFR and C-erbB2 differentially regulate Ral-1 translocation and activation[J].Lab Invest,2002 ,82(1) :71-78.
[13]Bal MM ,Das Radotra B ,Srinivasan R ,et al.Does c-erbB2 expression have a role in medulloblastoma prognosis[J] .Indian J Pathol Microbiol ,2006 ,49(4):535-539.
[14]Vizoso FJ, Corte MD.et al. Membranous levels of c-erbB-2 oncoprotein in gastric cancer: their relationship with clinicopathological parameters and their prognostic significance. Int J Biol Markers. 2004 Oct-Dec;19(4):268-74
[15]Lee SW, Kang SB.et al. Expression of c-erbB-2 and c-met proteins in gastric adenoma and adenocarcinoma. Korean J Gastroenterol. 2007 Mar;49(3):152-7.
[16]Wang DX,Fang DC,Liu WW.Induction of intestinal metaplasia in stomach of dogs and expression of tumor-related proteins in animal gastric mucosa lesions. Chin Med J,2000,113(1):336-341.
[17]Rask K,Nillson A,Bannstrom M,et al.Wnt-signalling pathway in ovarian epithelial tumors:increased expression ofβ-catenin and GSK-3β.BrJ Cancer,2003, 89(7):298-304.
[18]Park WS,Oh RR,Park JY,et al.Frequent somatic mutations of theβ-catenin gene in intestinal-type gastric cancer.Cancer Res,1999,59 (5):4257-4260.
[19]Field JK.The role of oncogenes and tumor-suppressor genes in the aetiology of oral,head and neck squamous cell carcinoma.J R Soc Med,1995,88(1): 35.
[20]Nakamura T,Pichel JG,Siaons LW,etal.An apoptotic defect in lens differ- entiation caused by human p53 is rescued by amutant allele.Proc Natl Acad USA,1995,92:6142.
[21]Koorey DJ,McCaughan GW,Trent RJ,et al.Exon eight APC mutations account for a disproportionate number of familial adenomatous polyposis families.Hum Mutat,1994,3(1):12-18.
[22]:Grace A, Butler D.et al. APC gene expression in gastric carcinoma: an immunohistochemical study. Appl Immunohistochem Mol Morphol. 2002 Sep;10(3):221-4.
[23] Wang D, Fang D.et al. Study of loss of heterozygosity at DCC and APC/MCC genetic loci of gastric cancer. Chin Med Sci J. 1999 Jun;14(2):107-11.
[24]Sato K, Tamura G, Frequent loss of expression without sequence mutations of the DCC gene in primary gastric cancer. Br J Cancer. 2001 Jul 20;85(2):199-203.
[25]Steele RJC, Thompson AM ,Hall PA ,et al.The p53 tumour suppressor gene[J] . British Journal of Surgery,1998,85 :1460-1467.
[26]Levine AJ , Momand J ,Finlay CA ,et al. The p53 tumour suppressor gene[J ] . Nature,1991 ,315 :453.
[27]Ichikawa A , Hotta T , Takagi N , et al. Mutations of p53 gene and their relation to disease progression in B-cell lymphoma[J]. Blood, 1992 , 79(10) :2701-2707.
[28] M?nig SP, Nolden B.etal. Clinical significance of nm23 gene expression in gastric cancer. 2007 Jul-Aug;27(4C):3029-33.
[29] Wang LB, Jiang ZN. Changes of histology and expression of MMP-2 and nm23-H1 in primary and metastatic gastric cancer. World J Gastroenterol. 2008 Mar 14;14(10):1612-6.
[30]Nomura H,Fujimoto N,Seiki M,et al.Enhanced production of matrix metalloproteinases and activation of matrix metalloproteinase 2 (gelatinase A)in human gastric carcinomas.Int J Cancer.1996 Feb 20; 69(1):9-16.
[31]Heider KH, Dammrich J, Skroch-Angel P, et al. Differential expression of CD44 variants intestinal and diffuse-type human gastric carcinomas and normal gastric mucosa [J]. Cancer Res, 1993, 53(8):4197 - 4203.
[32]Ham HJ, Ho LT, Chang JY, et al. Differential expression of the human metastasis adhesion molecule CD44v in normal and carcinomatous stomach mucosa of Chinese subjects[ J ]. Cancer, 1995, 75 (4):1065-1071.
[33]Mirecka J,Mark D, Schauer A,et al. Immunohistochemical localization of CD44 variants 5 and 6 in human gastric mucosa and gastric.
[34]Mayer B, Jauch KW, Gunthert U, et al. De-novo expression of CD44 and survival in gastric cancer [J].Lancet,1993,342 (8):1019 -1022.
[35]Hong RL,Lee WJ, Shun CT,et al.Expression of CD44 and its clinical implication in diffuse-type and intestinal-type gastrica denocarcinoma [J]. Oncology, 1995, 52 (4):334.
[36]Wu CY, Wu MS.et al. Clinicopathological significance of urokinase-type plasminogen activator genotypes in gastric cancer. Hepatogastroenterology. 2008 Sep-Oct;55(86-87):1890-4.
[37]Zhang FH, Zhou YN.et al. Expression of cyclooxygenase-2 and urokinase plasminogen activator in gastric carcinoma and the clinical significance. Zhonghua Yi Xue Za Zhi. 2008 Dec 16;88(46):3279-82
[38]Liu WT, Jiao HL.et al. Correlation of E-cadherin hypermethylation to tumorigenesis and development of gastric cancer. Ai Zheng. 2007 Nov;26(11):1199-203
[39]王东旭,房殿春,周晓东,等.胃癌组织5q微卫星不稳定性与APC/MCC基因杂合性缺失的研究.中华消化杂志,1999,19(2):107-110.
[40]Rhyu MG,Park WS,Jung YL,etal.Allelic deletions of MCC/APC and p53 are frequent late events in human gastric carcinogenesis. Gastroenterology, 1994,106: 1584-1587.
[41]Stricler JG,Zheng J,Shu Q,etal.p53 mutations and microsatellate instability in sporadic gastric cancer:when guardians fail.Cancer Res, 1994,54:4750-4755.
[42]Mironor NM,Aguelon AM,Potapovn GI,etal.Alterations of(CA)DNA repeats and tumor suppressor genes in human gastric cancer.Cancer Res,1994,54:41-44.
[43]Wang W,Luo HS,Yu BP.Telomerase and colorectal cancer.Shijie Huaren Xiaohua Zazhi,2000,8:800.
[44]唐发清,蒋海鹰,段朝军,等.鼻咽上皮癌变过程中端粒酶活性和端粒酶RNA的表达.中华病理学杂志,2001,30:125.
[45]Kim NW,Hruszkewycz AM.Telomerase activity modulation in theprevention of prostate cancer.Urology,2001,57(4Suppl1):148.
[46]LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Bairdand S, Korneluk RG. IAP-targeted therapies for cancer. Oncogene. 2008;27:6252–6275.
[47]Vucic D, Fairbrother WJ. The Inhibitor of Apoptosis Proteins as Therapeutic Targets in Cancer. Clin Cancer Res. 2007;13:5995–6000.
[48] Eckelman BP, Salvesen SG, Scott FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006;7:988–994.
[49] Vucic D, Fairbrother WJ. The Inhibitor of Apoptosis Proteins as Therapeutic Targets in Cancer. Clin Cancer Res. 2007;13:5995–6000.
[50]SongZ,YaoX,WuM.Directinteraction between survivin and Smac is essential for the antiapoptoticactivity of survivin during Taxol-induced apoptosis. J Biol Chem ,2003; 278 (25) :23130～40.
[51]Richter BW,Mir SS,Eiben LJ et al .Molecularclonin gofILP-2,A novel member of the inhibitor of apoptosis protein family. Mol Cell Biol ,2001; 21 (13) :4292～301.
[52]Eckelman BP, Salvesen SG, Scott FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006;7:988–994.
[53]Fulda S. Inhibitor of apoptosis proteins in hematological malignancies. Leukemia. 2009;23:467–76.
[54]Fotin-MleczekM, HenklerF,SamelD et al .A poptoticcrosstalk of TNF receptors:TNF-R-2 induces depletion of TRAF2 and IAP Proteins and accelerates TNF-R1-dependent activation of caspase-8. J Cell Sci ,2002; 115 ( Pt13 ) :2757～70.
[55]Sanna MG,daSilvaCorreiaJ,Ducrey OM et al .IAP suppression of apoptosis involves distinct mechanisms:the TAK1/JNK1 signaling cascade and caspase inhibition. Mol Cell Biol , 2002; 22 (6) :1754～66.
[56]Suga K, Yamamoto T, Yamada Y, et a.l Correlation between transcripti- onalexpression ofsurvivin isoforms and clinicopathological findings in human colorectal carcinomas [J]. OncolRep, 2005, 13: 891-897.
[57]McElenyKR, Watson RW, Coffey RN, et a.l Inhibitors of apoptosis proteins in prostate cancer cell lines [J].Prostate, 2002, 51: 133-140.
[58]Liu J, LiM, Xia S. Expression and clinical significance of antiapoptosis gene XIAP in prostate cancer [J]. Natl J Androl (中华男科), 2004, 10: 832-835.
[59]Jang JY, Kim HJ, Chi SG, et al. Frequent epigenetic inactivation of XAF1 by promotor hypermethylation in human colon cancers [J]. Korean JGastroentero,l2005,45: 285-293.
[60]MaTL, NiPH, Zhong J, etal. Low expression of XIAP-associated factor1 in human colorectal cancers [J]. Chin J Dig Dis, 2005,6:10-14.
[61]Roy N, Mahadevan MS, McLean M, et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. J.Cell, 1995, 80 (1) : 167～178.
[62] Xu D.G. et al. (1997a) Elevation of neuronal expression of NAIP reduces ischemic damage in the rat hippocampus. Nature Med., 3:, 997–1004.
[63]u D.G., Korneluk,R.G., Tamai,K., Wigle,N., Hakim,A., Mackenzie,A. and Robertson,G.S. (1997b) Distribution of neuronal apoptosis inhibitory protein-like immunoreactivity in the rat central nervous system. J. Comp. Neurol., 382:, 247–259.
[64]Abe s,Yamamoto K,Hasegawa M,et al.Bone marrow cells of myelodysplastic syndromes exhibit singnificat expression of apollion,livin and ILP-2 with reduction after transformation to overt leukemia.Leuk Res.2005 S,29(9):1095-6.
[65]孙鹏. AF1q基因、ILP-2与Smac在白血病中的表达及意义.[D].中国优秀硕士学位论文全文数据库,2007,(11).
[66]Yonesaka K, Tamura K, Kurata T, et a.l Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to adriamycin [J]. Int J Cancer,2005, in press.
[67]Hu Y, Cherton-HorvatG, DragowskaV, eta.l Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo[J]. Clin CancerRes,2003,9: 2826-2836.
[68]Carter BZ, Milella M, Tsao T, et al. Regulation and targeting of antiapoptotic XIAP in acutemyeloid leukemia[J]. Leukemia, 2003, 17: 2081-2089.
[69]Bilim V, Kasahara T, Hara N, et al. Role of XIAP in The malignant phenotype of transitional cell cancer(TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistant TCC in vitro[J]. Int J Cancer, 2003, 103: 29-37.
[70]Crnkovic-Mertens I, Hoppe-Seyler F, Butz K. Induction o fapoptosis intumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene [J]. Oncogene, 2003, 22:8330-8336.
[71]McEleny K, Coffey R, Morrissey C, et al. An antisense oligonucleotide to cIAP-1 sensitizes prostate cancer cells to fas and TNF alpha mediated apoptosis [J]. Prostate,2004, 59: 419-425.
[72]Wang XW, Fu LW. Inhibator of apoptosis proteins (IAP): new target of anticancer [J]. Chin Pharmacol Bull (中国药理学通报), 2004, 20: 129-133.
[73]Yang L, Mashima T, Sato S, et al. Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: therapeutic effect of a novel polyarginine-conjugated Smac peptide [J]. CancerRes, 2003, 63: 831-837.
[74]Sekine K, Hao Y, Suzuki Y, et al. HtrA2 cleaves Apollon and induces cell death by IAP-binding motif in Apollon-deficient cells [J]. Biochem Biophys Res Commun, 2005, 330: 279-285.
[75]anahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.
[76]aux DL, Korsmeyer SJ. Cell death in development. Cell. 1999;96(2):245–254.
[77]van Loo G, Saelens X, van Gurp M, MacFarlane M, Martin SJ, Vandenabeele P. The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. Cell Death Differ. 2002;9(10):1031–1042.
[78]Zou H, Li Y, Liu X, Wang X. An APAF-1. cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem. 1999;274(17):11549–11556.
[79]Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell. 1998;94(3):325–337.
[80] DU C , Fang M,Li Y,et al . Smac ,a mitochondrial protein that promotes Cytochrome-dependent caspase activation by elimination IAP inhibition [J]. Cell, 2000, 102(1) :33.
[81]Srinivasa MS ,Datta P ,Xun JU ,et al . Molecular determinants of thecaspase-promoting activity of Smac/ DIABLO and its role in the death receptor pathway[J] .Biol Chem ,2000 ,275 :36152.
[82]u C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102(1):33–42.
[83]hai J, Du C, Wu JW, Kyin S, Wang X, Shi Y. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature. 2000;406(6798):855–862.
[84]Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y. Structural basis of IAP recognition by Smac/DIABLO. Nature. 2000;408(6815):1008–1012.
[85]Srinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J, Lee RA, Robbins PD, Fernandes-Alnemri T, Shi Y, et al. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature. 2001;410(6824):112–116.
[86]Kashkar H, Haefs C, Shin H, Hamilton-Dutoit SJ, Salvesen GS, Kronke M, Jurgensmeier JM. XIAP-mediated caspase inhibition in Hodgkin's lymphoma-derived B cells. J Exp Med. 2003;198(2):341–347.
[87]Arnt CR, Chiorean MV, Heldebrant MP, Gores GJ, Kaufmann SH. Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ. J Biol Chem. 2002;277(46):44236–44243.
[88]Mizukawa K, Kawamura A, Sasayama T, Tanaka K, Kamei M, Sasaki M, Kohmura E. Synthetic Smac peptide enhances the effect of etoposide-induced apoptosis in human glioblastoma cell lines. J Neurooncol. 2006;77(3):247–255.
[89]Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG. A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science. 2004;305(5689):1471–1474.
[90]Bockbrader KM, Tan M, Sun Y. A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells. Oncogene. 2005;24(49):7381–7388.
[91]Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, et al. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell. 2007;131(4):682–693.
[92]Fulda S, Wick W, Weller M, Debatin KM. Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med. 2002;8(8):808–815.
[93]Zhao J, Jin J, Zhang X, Shi M, Dai J, Wu M, Wang R, Guo Y. Transfection of Smac sensitizes tumor cells to etoposide-induced apoptosis and eradicates established human hepatoma in vivo. Cancer Gene Ther. 2006;13(4):420–427.
[94]Yan Y, Mahotka C, Heikaus S, Shibata T, Wethkamp N, Liebmann J, Suschek CV, Guo Y, Gabbert HE, Gerharz CD, et al. Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas. Br J Cancer. 2004;91(7):1349–1357.
[95]Kempkensteffen C, Hinz S, Christoph F, Krause H, Magheli A, Schrader M, Schostak M, Miller K, Weikert S. Expression levels of the mitochondrial IAP antagonists Smac/DIABLO and Omi/HtrA2 in clear-cell renal cell carcinomas and their prognostic value. J Cancer Res Clin Oncol. 2008;134(5):543–550.
[96]Mizutani Y, Nakanishi H, Yamamoto K, Li YN, Matsubara H, Mikami K, Okihara K, Kawauchi A, Bonavida B, Miki T. Downregulation of Smac/DIABLO expression in renal cell carcinoma and its prognostic significance. J Clin Oncol. 2005;23(3):448–454.
[97]Hofmann HS, Simm A, Hammer A, Silber RE, Bartling B. Expression of inhibitors of apoptosis (IAP) proteins in non-small cell human lung cancer. J Cancer Res Clin Oncol. 2002;128(10):554–560.
[98]Hu Y, Cherton-Horvat G, Dragowska V, Baird S, Korneluk RG, Durkin JP, Mayer LD, LaCasse EC. Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo. Clin Cancer Res. 2003;9(7):2826–2836.
[99]Bao ST, Gui SQ, Lin MS. Relationship between expression of Smac and Survivin and apoptosis of primary hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2006;5(4):580–583.
[100]Espinosa M, Cantu D, Lopez CM, De la Garza JG, Maldonado VA, Melendez-Zajgla J. SMAC is expressed de novo in a subset of cervical cancer tumors. BMC Cancer. 2004;4:84.
[101]Arellano-Llamas A, Garcia FJ, Perez D, Cantu D, Espinosa M, De la Garza JG, Maldonado V, Melendez-Zajgla J. High Smac/DIABLO expression is associated with early local recurrence of cervical cancer. BMC Cancer. 2006;6:256.
[102]Shibata T, Mahotka C, Wethkamp N, Heikaus S, Gabbert HE, Ramp U. Disturbed expression of the apoptosis regulators XIAP, XAF1, and Smac/DIABLO in gastric adenocarcinomas. Diagn Mol Pathol. 2007;16(1):1–8.
[103]Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG. Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol. 2001;3(2):128–133.
[104]Yang L,Mashima T ,Sato S,et al. Predominant Suppression of Apoptosome by Inhibitor of Apoptosis Protern in Non-small Cell Lung Cancer H460 Cells: Therapeutic Effect of a Novel Polyarginine-conjugated Smac Peptide.Cancer Res,2003,63(4):831-837.
[105]Nagamine M, Okumura T, Tanno S,et al. PPAR gamma ligand-induced apoptosis through a p53-dependent mechanism in human gastric cancer ce1ls.Cancer Sci.2003;94(4):338-343.
[106]Baek SJ, Wilson LC, His LC,etal.Troglitazone,a peroxisome proliferator-activated receptor gamma (PPAR gamma)ligand, selectively induces the early growth response-1 gene independently of PPAR gamma. A novel mechanism for its anti-tumorigenic activity.J Biol Chem. 2003;278(8):5845-5853.
[107]Strakova N, Ehrmann J, Dzubak P,et al. The synthetic ligand of peroxisome proliferator-activated receptor-gamma ciglitazone affects human glioblastoma celllines.Pharmacol Exp Ther. 2004;309(3):1239-1247.
[108]Han S, Sidell N, Fisher PB, et al. Up-regulation of p21 gene expressionby peroxisome proliferator-activated receptor gamma in human lung carcinoma cells.Clin Cancer Res.2004;10(6):1911一1919.
[109]Koga H, Sakisaka S, Harada M, et al.Involvement of p21(WAF1/Cip1), p27(Kipl), and p18(INK4c) in troglitazone-induced cell-cycle arrest in human hepatoma cell lines.Hepatology. 2001;33(5):1087-1097.
[110]潘华锋,陈孝平.Ciglitazone抑制人肝癌HepG2细胞增殖活性的实验研究[J].中华实验外科杂志,2004,21(8):934-936.
[111]孙象军.苯丁酸钠及二甲基甲酰胺对乳腺癌细胞增殖抑制及诱导分化的实验研究.[D].中国优秀博学位论文全文数据库,2007,(11).
[112]Samid D,Hudgins WR,Shack S,et al.Phenylacetate and phenylbutyrate as novel,nontoxic differentiation inducers[J].Adv Exp Med Biol.1997,400:501-505.
[113] Baker MJ, Brem S,etal. Complete response of a recurrent, multicentric malignant glioma in a patient treated with phenylbutyrateJ Neurooncol. 2002 Sep;59(3):239-42.
[114] Calvaruso G, CarabillòM,et al. Sodium phenylbutyrate induces apoptosis in human retinoblastoma Y79 cells: the effect of combined treatment with the topoisomerase I-inhibitor topotecan. Int J Oncol. 2001 Jun;18(6):1233-7.
[115]Yu KH,Weng LJ,Fu S,et al.Augmentation of phenylbutyrate-induced differentiation of myeloid leukemia cells using all-trans retinoid acid[J]. Leukemia, 1999,13:1258-1265.
[116] Gore SD, Samid D, Weng LJ. Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells. Clin Cancer Res. 1997 Oct;3(10):1755-62
[117] Meng M, Jiang JM, Liu H,et al. Effects of sodium phenylbutyrate on differentiation and induction of the P21WAF1/CIP1 anti-oncogene in human liver carcinoma cell lines.Chin J Dig Dis. 2005;6(4):189-92.
[118] Gao J, Ruan X,etal. The effect of sodium phenylbutyrate to agents used in induction chemotherapy on laryngeal carcinoma cells Hep-2 in vitro.Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2005 Aug;19(15):680-2.