细胞凋亡抑制蛋白2在胰腺癌中的表达及其与胰腺癌吉西他滨化疗的关系
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摘要
目的
本研究观察细胞凋亡抑制蛋白2(cell inhibitor of apoptosis protein 2,C-IAP2)在胰腺癌组织以及胰腺癌细胞中的表达情况并分析其与病理分级、临床分期之间的关系,并进一步阐明C-IAP2的表达与吉西他滨化疗促胰腺癌凋亡作用和胰腺癌吉西他滨化疗耐药的关系。
方法
1.收集本院普通外科2005年8月至2008年3月手术切除的胰腺癌组织标本32例,癌旁正常胰腺组织标本18例,运用免疫组织化学染色方法观察C-IAP2在胰腺癌组织以及癌旁正常胰腺组织的表达情况,分析C-IAP2的表达水平与胰腺癌组织的病理分级和临床分期之间的关系。Western blot进一步观察C-IAP2在低分化的胰腺癌PANC-1细胞、中分化的胰腺癌AsPC-1细胞、高分化的胰腺癌BxPC-3细胞中的表达情况,分析C-IAP2的表达水平与胰腺癌细胞的病理分级之间的关系。
2.研究吉西他滨体外诱导人胰腺癌PANC-1细胞凋亡作用和分子机理,MTT比色法测定细胞增殖活性,透射电子显微镜观察凋亡细胞形态,AnnexinV-PI双标记法流式细胞术检测细胞凋亡率,RT-PCR分析细胞C-IAP2的mRNA表达,Western blot法检测不同浓度吉西他滨作用后C-IAP2、第二线粒体来源的半胱氨酸天冬氨酸蛋白水解酶激活剂(second mitochondria-derived activator of caspase,Smac)、Bcl(B cell lymphoma)-2和Bax的表达变化,分光光度法检测Caspase-3、Caspase-9活性。
3.采用间歇浓度梯度递增法诱导胰腺癌PANC-1细胞株对吉西他滨耐药,检测其生物学性状变化,免疫荧光和免疫印迹法对比观察C-IAP2活性变化。
结果
1.C-IAP2在胰腺癌组织均有表达(32/32,100%)、癌旁正常胰腺组织(8/18,44.4%)中有表达,胰腺癌组织中表达水平显著强于癌旁正常胰腺组织。C-IAP2的表达强度在不同分化程度的肿瘤组织中的差异有统计学意义(P <0.05)。C-IAP2在低分化的胰腺癌细胞PANC-1中呈高表达,而在中分化和高分化的胰腺癌细胞AsPC-1和BxPc-3中表达较低(P <0.05)。
2.MTT比色法测定显示:吉西他滨抑制人胰腺癌细胞株PANC-1增殖,呈浓度依赖性;其IC50值为5.79ug/ml。AnnexinV-PI双标记法FCM分析、透射电子显微镜观察的结果证实:吉西他滨具有诱导人胰腺癌PANC-1细胞株凋亡作用。RT-PCR分析发现吉西他滨能显著下调PANC-1细胞C-IAP2的mRNA表达,Western blot分析发现吉西他滨能显著下调胰腺癌细胞PANC-1的C-IAP2、Bcl-2蛋白表达水平,上调Smac、Bax蛋白表达水平,分光光度法分析发现吉西他滨作用后胰腺癌PANC-1细胞的Caspase-3、Caspase-9活性显著升高。
3.药物培养3个月后,得到稳定传代的PANC-1/Gem耐药细胞株,其形态学、生长特征等均发生了明显变化,细胞变圆、体积缩小、颗粒样物质增多及细胞倍增时间延长,对吉西他滨、5-氟尿嘧啶、阿霉素和丝裂霉素的耐药性均显著增加;耐药细胞PANC-1/Gem的C-IAP2的蛋白表达水平也明显增高。
结论
1.C-IAP2在胰腺癌组织中的表达水平以及阳性率均显著高于癌旁的正常胰腺组织,推测C-IAP2的表达升高可能在胰腺癌的发生中起一定作用。C-IAP2的表达强度在不同分化程度的肿瘤组织和细胞中的差异有统计学意义,通过检测术后组织标本中C-IAP2的表达有可能对胰腺癌的恶性程度作出预测。
2.吉西他滨可诱导人胰腺癌细胞PANC-1凋亡,作用与其下调凋亡抑制因子C-IAP2、Bcl-2表达水平,上调促凋亡因子Smac、Bax表达水平,活化Caspase- 3、Caspase-9有关。
3.间歇浓度梯度递增法可诱导胰腺癌PANC-1细胞株对吉西他滨耐药,PANC-1/Gem有多药耐药现象,C-IAP2在耐药过程中起一定作用。
Objective
This study was to observe the expression of C-IAP2 in pancreatic carcinoma and pancreatic cancer cells and to analyze the relationship between its expression and pathological grade, clinical stage,and to further explore the relationship between the expression of C-IAP2 and the pro-apoptotic role of gemcitabine chemotherapy in pancreatic cancer cell,and to investigate the relationship between C-IAP2 expression and gemcitabine chemotherapy resistance in pancreatic cancer. Methods
1.32 cases of pancreatic cancer specimens and 18 cases of adjacent tissues from August 2005 to March 2008 in Union Hospital of Fujian Medical University were examined by immunohistochemistry and the relationship of C-IAP2 expression to the clinical stage and pathological grade was analyzed.Using Western blot to further observe the expression of C-IAP2 in the poorly differentiated PANC-1, in the moderately differentiation of AsPC-1, well-differentiated BxPC-3 pancreatic cancer cell lines,the relations between the expression of C-IAP2 levels and the pathological class of pancreatic cancer cells was analyzed.
2.To study Gemcitabine in vitro inducing human pancreatic cancer cell PANC-1 apoptosis and its molecular mechanism,cell proliferation activity was analyzed by MTT colorimetric assay;cell morphology was observed by transmission electron microscopy;cell apoptosis rate was observed by PI staining flow cytometry;C-IAP2 mRNA expression was analyzed by RT-PCR;C-IAP2, Smac, Bcl-2 and Bax protein expression was analyzed by Western blot;Caspase-3,Caspase-9 activity were detected by spectrophotometry.
3.A gemcitabine-resistant pancreatic cancer cell line(PANC-1)was obtained b y gradient increase of concentration.It’s biological properties and activity of C-IAP2 were detected.
Results
1.C-IAP2 were expressed in pancreatic carcinoma (32/32,100%), adjacent normal pancreatic tissue (8/18, 44.4%).The C-IAP2 expression level of pancreatic cancer significantly stronger than the normal pancreatic tissue adjacent to cancer.The differences of C-IAP2 expression level at different degree of differentiation of tumor tissue were significant (P<0.05).C-IAP2 was highly expressed in poorly differentiated pancreatic cancer cells PANC-1,and expressed lowly in the moderate differentiation and well-differentiated pancreatic cancer cells AsPC-1 and BxPc-3.
2.MTT colorimetric assay showed:Gemcitabine inhibited pancreatic cancer cell line PANC-1 proliferation with a dose-dependent manner;its value of IC50 5.79ug/ml. Gemcitabine inducing pancreatic cancer cell line PANC-1 apoptosis was confirmed by FCM analysis of PI staining and transmission electron microscopy.RT-PCR analysis showed that gemcitabine significantly reduced expression of C-IAP2 mRNA in PANC-1 cells,.Western blot analysis showed that gemcitabine significantly reduced C-IAP2,Bcl-2 protein expression level,increased Smac,Bax protein expression level in pancreatic cancer cells PANC-1.Spectrophotometric analysis showed that gemcitabine significantly increased Caspase-3, Caspase-9 activity in pancreatic cancer cells PANC-1.
3.Stable drug resistant PANC-1/Gem cell strain was established by culturing with gemcitabine for 3 months.The morphology and growth characteristics of the cell strain was changed remarkably.The cells shrinked and became rounder,granular substance increased;and the doubling-time was prolonged.Resistance of the cell line to gemcitabine,fluorouracil,adriamycin,and mytomycin sinnificantly increased.The C-IAP2 protein expression levels of the drug-resistant cells were significantly increased.
Conclusions
1.The expression level of C-IAP2 as well as the positive rate in pancreatic carcinoma were significantly higher than the adjacent normal pancreatic tissue,high expression of C-IAP2 may play a role to some extent in pancreatic cancer development.There was significant difference of C-IAP2 expression in different differentiation of pancreatic cancer.Expression of C-IAP2 may predict the degree of malignancy in pancreatic cancer tissues.
2.The apoptosis of human pancreatic cancer PANC-1 cell could be induced by gemcitabine.Gemcitabine pro-apoptotic role may be due to decrease of C-IAP2 and Bcl-2 expression levels,increase of Smac,Bax expression levels,and activation of Caspase-3, Caspase-9.
3.Stable drug resistant PANC-1/Gem cell strain could be obtained by intermittent incremental concentrations of gemcitabine.PANC-1/Gem have multiple drug resistance situation.C-IAP2 may play a role to some extent in the process of drug resistance.
本研究观察细胞凋亡抑制蛋白2(cell inhibitor of apoptosis protein 2,C-IAP2)在胰腺癌组织以及胰腺癌细胞中的表达情况并分析其与病理分级、临床分期之间的关系,并进一步阐明C-IAP2的表达与吉西他滨化疗促胰腺癌凋亡作用和胰腺癌吉西他滨化疗耐药的关系。
方法
1.收集本院普通外科2005年8月至2008年3月手术切除的胰腺癌组织标本32例,癌旁正常胰腺组织标本18例,运用免疫组织化学染色方法观察C-IAP2在胰腺癌组织以及癌旁正常胰腺组织的表达情况,分析C-IAP2的表达水平与胰腺癌组织的病理分级和临床分期之间的关系。Western blot进一步观察C-IAP2在低分化的胰腺癌PANC-1细胞、中分化的胰腺癌AsPC-1细胞、高分化的胰腺癌BxPC-3细胞中的表达情况,分析C-IAP2的表达水平与胰腺癌细胞的病理分级之间的关系。
2.研究吉西他滨体外诱导人胰腺癌PANC-1细胞凋亡作用和分子机理,MTT比色法测定细胞增殖活性,透射电子显微镜观察凋亡细胞形态,AnnexinV-PI双标记法流式细胞术检测细胞凋亡率,RT-PCR分析细胞C-IAP2的mRNA表达,Western blot法检测不同浓度吉西他滨作用后C-IAP2、第二线粒体来源的半胱氨酸天冬氨酸蛋白水解酶激活剂(second mitochondria-derived activator of caspase,Smac)、Bcl(B cell lymphoma)-2和Bax的表达变化,分光光度法检测Caspase-3、Caspase-9活性。
3.采用间歇浓度梯度递增法诱导胰腺癌PANC-1细胞株对吉西他滨耐药,检测其生物学性状变化,免疫荧光和免疫印迹法对比观察C-IAP2活性变化。
结果
1.C-IAP2在胰腺癌组织均有表达(32/32,100%)、癌旁正常胰腺组织(8/18,44.4%)中有表达,胰腺癌组织中表达水平显著强于癌旁正常胰腺组织。C-IAP2的表达强度在不同分化程度的肿瘤组织中的差异有统计学意义(P <0.05)。C-IAP2在低分化的胰腺癌细胞PANC-1中呈高表达,而在中分化和高分化的胰腺癌细胞AsPC-1和BxPc-3中表达较低(P <0.05)。
2.MTT比色法测定显示:吉西他滨抑制人胰腺癌细胞株PANC-1增殖,呈浓度依赖性;其IC50值为5.79ug/ml。AnnexinV-PI双标记法FCM分析、透射电子显微镜观察的结果证实:吉西他滨具有诱导人胰腺癌PANC-1细胞株凋亡作用。RT-PCR分析发现吉西他滨能显著下调PANC-1细胞C-IAP2的mRNA表达,Western blot分析发现吉西他滨能显著下调胰腺癌细胞PANC-1的C-IAP2、Bcl-2蛋白表达水平,上调Smac、Bax蛋白表达水平,分光光度法分析发现吉西他滨作用后胰腺癌PANC-1细胞的Caspase-3、Caspase-9活性显著升高。
3.药物培养3个月后,得到稳定传代的PANC-1/Gem耐药细胞株,其形态学、生长特征等均发生了明显变化,细胞变圆、体积缩小、颗粒样物质增多及细胞倍增时间延长,对吉西他滨、5-氟尿嘧啶、阿霉素和丝裂霉素的耐药性均显著增加;耐药细胞PANC-1/Gem的C-IAP2的蛋白表达水平也明显增高。
结论
1.C-IAP2在胰腺癌组织中的表达水平以及阳性率均显著高于癌旁的正常胰腺组织,推测C-IAP2的表达升高可能在胰腺癌的发生中起一定作用。C-IAP2的表达强度在不同分化程度的肿瘤组织和细胞中的差异有统计学意义,通过检测术后组织标本中C-IAP2的表达有可能对胰腺癌的恶性程度作出预测。
2.吉西他滨可诱导人胰腺癌细胞PANC-1凋亡,作用与其下调凋亡抑制因子C-IAP2、Bcl-2表达水平,上调促凋亡因子Smac、Bax表达水平,活化Caspase- 3、Caspase-9有关。
3.间歇浓度梯度递增法可诱导胰腺癌PANC-1细胞株对吉西他滨耐药,PANC-1/Gem有多药耐药现象,C-IAP2在耐药过程中起一定作用。
Objective
This study was to observe the expression of C-IAP2 in pancreatic carcinoma and pancreatic cancer cells and to analyze the relationship between its expression and pathological grade, clinical stage,and to further explore the relationship between the expression of C-IAP2 and the pro-apoptotic role of gemcitabine chemotherapy in pancreatic cancer cell,and to investigate the relationship between C-IAP2 expression and gemcitabine chemotherapy resistance in pancreatic cancer. Methods
1.32 cases of pancreatic cancer specimens and 18 cases of adjacent tissues from August 2005 to March 2008 in Union Hospital of Fujian Medical University were examined by immunohistochemistry and the relationship of C-IAP2 expression to the clinical stage and pathological grade was analyzed.Using Western blot to further observe the expression of C-IAP2 in the poorly differentiated PANC-1, in the moderately differentiation of AsPC-1, well-differentiated BxPC-3 pancreatic cancer cell lines,the relations between the expression of C-IAP2 levels and the pathological class of pancreatic cancer cells was analyzed.
2.To study Gemcitabine in vitro inducing human pancreatic cancer cell PANC-1 apoptosis and its molecular mechanism,cell proliferation activity was analyzed by MTT colorimetric assay;cell morphology was observed by transmission electron microscopy;cell apoptosis rate was observed by PI staining flow cytometry;C-IAP2 mRNA expression was analyzed by RT-PCR;C-IAP2, Smac, Bcl-2 and Bax protein expression was analyzed by Western blot;Caspase-3,Caspase-9 activity were detected by spectrophotometry.
3.A gemcitabine-resistant pancreatic cancer cell line(PANC-1)was obtained b y gradient increase of concentration.It’s biological properties and activity of C-IAP2 were detected.
Results
1.C-IAP2 were expressed in pancreatic carcinoma (32/32,100%), adjacent normal pancreatic tissue (8/18, 44.4%).The C-IAP2 expression level of pancreatic cancer significantly stronger than the normal pancreatic tissue adjacent to cancer.The differences of C-IAP2 expression level at different degree of differentiation of tumor tissue were significant (P<0.05).C-IAP2 was highly expressed in poorly differentiated pancreatic cancer cells PANC-1,and expressed lowly in the moderate differentiation and well-differentiated pancreatic cancer cells AsPC-1 and BxPc-3.
2.MTT colorimetric assay showed:Gemcitabine inhibited pancreatic cancer cell line PANC-1 proliferation with a dose-dependent manner;its value of IC50 5.79ug/ml. Gemcitabine inducing pancreatic cancer cell line PANC-1 apoptosis was confirmed by FCM analysis of PI staining and transmission electron microscopy.RT-PCR analysis showed that gemcitabine significantly reduced expression of C-IAP2 mRNA in PANC-1 cells,.Western blot analysis showed that gemcitabine significantly reduced C-IAP2,Bcl-2 protein expression level,increased Smac,Bax protein expression level in pancreatic cancer cells PANC-1.Spectrophotometric analysis showed that gemcitabine significantly increased Caspase-3, Caspase-9 activity in pancreatic cancer cells PANC-1.
3.Stable drug resistant PANC-1/Gem cell strain was established by culturing with gemcitabine for 3 months.The morphology and growth characteristics of the cell strain was changed remarkably.The cells shrinked and became rounder,granular substance increased;and the doubling-time was prolonged.Resistance of the cell line to gemcitabine,fluorouracil,adriamycin,and mytomycin sinnificantly increased.The C-IAP2 protein expression levels of the drug-resistant cells were significantly increased.
Conclusions
1.The expression level of C-IAP2 as well as the positive rate in pancreatic carcinoma were significantly higher than the adjacent normal pancreatic tissue,high expression of C-IAP2 may play a role to some extent in pancreatic cancer development.There was significant difference of C-IAP2 expression in different differentiation of pancreatic cancer.Expression of C-IAP2 may predict the degree of malignancy in pancreatic cancer tissues.
2.The apoptosis of human pancreatic cancer PANC-1 cell could be induced by gemcitabine.Gemcitabine pro-apoptotic role may be due to decrease of C-IAP2 and Bcl-2 expression levels,increase of Smac,Bax expression levels,and activation of Caspase-3, Caspase-9.
3.Stable drug resistant PANC-1/Gem cell strain could be obtained by intermittent incremental concentrations of gemcitabine.PANC-1/Gem have multiple drug resistance situation.C-IAP2 may play a role to some extent in the process of drug resistance.
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2.王晓红,符立悟.凋亡抑制蛋白家族与肿瘤治疗的研究进展.药学学报.2006,41:103-107.
3. Deveraux QL, RoyN, et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases.EMBO J,1998, 17: 2215 - 23.
4. Suzuki Y, Nakabayashi Y,et al. X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and caspase-7 in distinct modes.J Biol Chem, 2001, 276(29): 27058-63.
5. SuzukiY,NakabayashiY,et al.Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death.Proc Natl Acad Sci USA ,2001,98:8662 -7.
6. Hakem RA,Hakem GS,et al.Differential requirement for caspase 9 in apoptotic pathways in vivo.Cell,1998, 94:339-52.
7. Li F, Ambrosini G,et al.Control of apoptosis and mitotic spindle checkpoint by survivin. Nature,1998,396:580-4.
8. SannaMG, Da silva Correia J, et al. IAP suppression of apoptosis involves distinct mechanisms: the TAKI/JNKI signaling cascade and caspase inhibition.MolCell Biol, 2002, 22: 1754 -66.
9.王婷玉,李俊.凋亡抑制蛋白的研究进展.安微医药.2005,9(6):402-406.
10. Nachmias B, Ashhab Y,et,al. The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer. Semin Cancer Biol. 2004;14(4):231-43.
11. Deveraux QL, Reed JC. IAP family proteins--suppressors of apoptosis. Genes Dev. 1999;13(3):239-52.
12. McEleny KR, Watson RW, Inhibitors of apoptosis proteins in prostate cancer cell lines. Prostate. 2002;51(2):133-40.
13.赵宝锋,刘建香.细胞凋亡抑制蛋白:肿瘤治疗的障碍与靶点.医学分子生物学杂志.2005,2(5):380-384.
14. Wu G, Chai J,et al.Structural basis of IAP recognition by Smac/DIABLO.Nature. 2000;408(6815):1008-12.
15. Shi Y. A conserved tetrapeptide motif: potentiating apoptosis through IAP-binding. Cell Death Differ.2002;9(2):93-5.
16. Schimmer AD. Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice.Cancer Res.2004;64(20):7183-90.
17. Yang L, Cao Z,et al. Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy.Cancer Res.2003;63(20):6815-24.
18. Li CJ, Friedman DJ,et al.Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein.Science.1995;268(5209):429-31.
19. Sun H, Nikolovska-Coleska Z, Structure-based design, synthesis and biochemical testing of novel and potent Smac peptido-mimetics. Bioorg Med Chem Lett. 2005;15(3):793-7.
20. Bin L,Mei H. Livin /ML-IAP as a new target for cancer treatment.Cancer Letters, 2007, 250 (2):168-176.
21. Schmolinger JC,Vonderheide RH,et al. Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction.Proc Natl Acad Sci USA,2003,100(6):3398-3403.
22. Hariu H, Hirohashi Y,et al. Aberrant expression and potency as a cancer immunotherapy target of inhibitor of apoptosis protein family, livin /ML-IAP inlung cancer.Clin CancerRes,2005,11(3):1000-1009.
23. Crnkovió2Mertens I,WagenerN, Semzow J,et al.Targeted inhibition of Livin resensitizes renal cancer cells towards apoptosis.Cell Mol Life Sci, 2007, 64: 1137 -1144.
24.俞浩钢,腾理送. Livin抗凋亡机制与肿瘤.临床肿瘤学杂志.2008,13(6):559-562.
25. Nam NH, Parang K.Current targets for anticancer drug discovery.Curr Drug Targets,2003,4(2):159-179.
26. AndersenMH, thor SP. Survivin: a universal tumor antigen.Histol Histopathol, 2002,17(2):669-675.
27.陈涛,田伏洲,等. Survivin反义寡核苷酸诱导肝癌细胞凋亡的作用.中华肝脏病杂志, 2003, 13 (9):546 -549.
28.巴一, Reisfeld Ralph A. Survivin反义寡核苷酸对小鼠肺癌的生长抑制作用.同济大学学报(医学版),2005, 26(2):1-4.
29.王晓梅,王一平,等.生存素反义寡核苷酸对胃癌细胞株SGC-7901生长的影响.实用癌症杂志,2005,20(1):24-27.
30.戴德坚,陆才德,等.靶向抑制survivin对胰腺癌细胞增殖和凋亡效应的影响.中华医学杂志,2004,84(22):1894-1898.
31.阮菲,解先宽,等. Survivin反义寡核苷酸对卵巢癌耐药细胞COC1/DDP抑制的实验研究.癌症,2004,23(8):896-899.
32.刘德权,段体德,等.Survivin反义核酸对乳腺癌细胞增殖的影响.昆明医学院学报, 2005,26(3):45-50.
33. Zamecnik PC,StephensonML.Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Nati Acad Sci, 1978, 75(1):280-284.
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35. O’ConnorDS, Grossman D, et al.Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci USA, 2000,97(24):13103-13107.
36. Reker S,Becker JC, et al.HLA-B35-restricted immune responses against survivin in cancer patients.Int JCancer,2004,108(6):937-941.
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38.李莉萍,梁念慈,等.存活素siRNA表达质粒的构建及其对MCF-7细胞细胞周期和增殖的调控.癌症, 2004,23 (7):742-7481.
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