组织芯片技术检测SIRT6蛋白在结肠癌组织中的表达及其临床意义
|
摘要
目的:探讨NAD依赖性蛋白脱乙酰基酶sirtuin-6 (SIRT6)蛋白在结肠癌组织中的表达及其与结肠癌患者临床病理参数之间的关系,阐明SIRT6蛋白在结肠癌发生发展中的作用。方法:选取术前均未行放化疗的100例结肠癌患者的结肠癌组织和癌旁组织,采用组织芯片技术和免疫组织化学SP法检测结肠癌组织和癌旁组织中SIRT6蛋白表达水平,采用秩和检验分析SIRT6蛋白表达水平与结肠癌患者临床病理参数的关系,采用Kaplan-Meier生存曲线、单因素和多因素生存分析法分析结肠癌患者临床病理参数与预后的关系。结果:SIRT6蛋白在结肠癌组织细胞核和胞浆中的表达水平均明显高于癌旁组织(Z=-4.603,P=0.000;Z=-7.610,P=0.000)。Kaplan-Meier单因素和多因素分析,细胞核中SIRT6蛋白高表达的结肠癌患者预后更好且是其独立预后影响因子(HR=2.345,P=0.003),年龄较小及T、N分期较低的患者生存率更高(HR=0.394,P=0.004;HR=2.301,P=0.012;HR=2.423,P=0.048),细胞浆中SIRT6蛋白高表达与结肠癌患者预后无关联性(HR=1.309,P=0.333)。结论:SIRT6蛋白在结肠癌细胞核中高表达可作为结肠癌预后良好的评价指标。
Objective:To investigate the expression of NAD-dependent protein deacetylase sirtuin-6(SIRT6)protein in the colon cancer tissue and the association between its expression and the clinicopathological parameters of the patients with colon cancer,and to elucidate the effect of the SIRT6 protein in the occurrence and development of colon cancer.Methods:The colon cancer tissue and the paracancerous tissue obtained from 100 patients who did not receive radiotherapy and chemotherapy before operation were selected.The expression levels SIRT6 protein in colon cancer tissue and paracancerous tissue were detected by tissue microarray technique and immunohistochemical SP method.The relationships between the expression of SIRT6 and the clinicopathological parameters of the patents with colon cancer were analyzed with rank sum test.Kaplan-Meier survival curre,univariate analysis and multivariate survival analysis were used to investigate the relationships between the clinicopathological parameters and the prognosis in the patients with colon cancer.Results:The expression levels of SIRT6 in cytoplasm and nucleus in colon cancer tissue were significantly higher than those in paracancerous tissue(Z=-4.603,P=0.000;Z=-7.610,P=0.000).The Kaplan-Meier univariate and multivariate analysis showed that the prognosis of the patients with high expression of SIRT6 in the nucleus was better,and the expression of SIRT6 was identified as the independent prognostic factor of colon cancer(HR=2.345,P=0.003);the patients with younger age,lower T and N stages had higher survival rates(HR=0.394,P=0.004;HR=2.301,P=0.012;HR=2.423,P=0.048);there was no correlation between the high expression of SIRT6 in cytoplasm and the prognosis(HR=1.309,P=0.333)of the patients with colon cancer.Conclusion:SIRT6 protein is highly expressed in the nucleus of colon cancer and it can be used as a good prognostic indicator for colon cancer.
Objective:To investigate the expression of NAD-dependent protein deacetylase sirtuin-6(SIRT6)protein in the colon cancer tissue and the association between its expression and the clinicopathological parameters of the patients with colon cancer,and to elucidate the effect of the SIRT6 protein in the occurrence and development of colon cancer.Methods:The colon cancer tissue and the paracancerous tissue obtained from 100 patients who did not receive radiotherapy and chemotherapy before operation were selected.The expression levels SIRT6 protein in colon cancer tissue and paracancerous tissue were detected by tissue microarray technique and immunohistochemical SP method.The relationships between the expression of SIRT6 and the clinicopathological parameters of the patents with colon cancer were analyzed with rank sum test.Kaplan-Meier survival curre,univariate analysis and multivariate survival analysis were used to investigate the relationships between the clinicopathological parameters and the prognosis in the patients with colon cancer.Results:The expression levels of SIRT6 in cytoplasm and nucleus in colon cancer tissue were significantly higher than those in paracancerous tissue(Z=-4.603,P=0.000;Z=-7.610,P=0.000).The Kaplan-Meier univariate and multivariate analysis showed that the prognosis of the patients with high expression of SIRT6 in the nucleus was better,and the expression of SIRT6 was identified as the independent prognostic factor of colon cancer(HR=2.345,P=0.003);the patients with younger age,lower T and N stages had higher survival rates(HR=0.394,P=0.004;HR=2.301,P=0.012;HR=2.423,P=0.048);there was no correlation between the high expression of SIRT6 in cytoplasm and the prognosis(HR=1.309,P=0.333)of the patients with colon cancer.Conclusion:SIRT6 protein is highly expressed in the nucleus of colon cancer and it can be used as a good prognostic indicator for colon cancer.
引文
[1]GERTLER A A,COHEN H Y.SIRT6,aprotein with many faces[J].Biogerontology,2013,14(6):629-639.
[2]MICHISHITA E,MCCORD R A,BERBER E,et al.SIRT6is a histone H3lysine 9deacetylase that modulates telomeric chromatin[J].Nature,2008,452(7186):492-496.
[3]KAWAHARA T L,MICHISHITA E,ADLER A S,et al.SIRT6links histone H3lysine 9deacetylation to NF-kappaB-dependent gene expression and organismal life span[J].Cell,2009,136(1):62-74.
[4]TANG Y L,ZHOU Y,WANG Y P,et al.SIRT6/NF-kappa B signaling axis in ginsenoside Rg1-delayed hematopoietic stem/progenitor cell senescence[J].Int J Clin Exp Pathol,2015,8(5):5591-5596.
[5]KUGEL S,MOSTOSLAVSKY R.Chromatin and beyond:the multitasking roles for SIRT6[J].Trends Biochem Sci,2014,39(2):72-81.
[6]ZHONG L,D’URSO A,TOIBER D,et al.The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha[J].Cell,2010,140(2):280-293.
[7]CARDUS A,URYGA A K,WALTERS G,et al.SIRT6protects human endothelial cells from DNA damage,telomere dysfunction,and senescence[J].Cardiovasc Res,2013,97(3):571-579.
[8]KANFI Y,PESHTI V,GIL R,et al.SIRT6protects against pathological damage caused by diet-induced obesity[J].Aging Cell,2010,9(2):162-173.
[9]LIAO C Y,KENNEDY B K.Will the real aging Sirtuin please stand up?[J].Cell Res,2012,22(8):1215-1217.
[10]SHUN C T,LIN S K,HONG C Y,et al.Sirtuin 6modulates hypoxia-induced autophagy in nasal polyp fibroblasts via inhibition of glycolysis[J].Am J Rhinol Allergy,2016,30(3):179-185.
[11]SEBASTIN C,ZWAANS B M,SILBERMAN D M,et al.The histone deacetylase SIRT6is a tumor suppressor that controls cancer metabolism[J].Cell,2012,151(6):1185-1199.
[12]GARCIA-PETERSON L M,NDIAYE M A,Singh C K,et al.SIRT6 histone deacetylase functions as a potential oncogene in human melanoma[J].Genes Cancer,2017,8(9/10):701-712.
[13]MING M,HAN W N,ZHAO B Z,et al.SIRT6promotes COX-2expression and acts as an oncogene in skin cancer[J].Cancer Res,2014,74(20):5925-5933.
[14]LIU Y W,XIE Q R,WANG B S,et al.Inhibition of SIRT6in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics[J].Protein Cell,2013,4(9):702-710.
[15]LEE N,RYU H G,KWON J H,et al.SIRT6depletion suppresses tumor growth by promoting cellular senescence induced by DNA damage in HCC[J].PLoS One,2016,11(11):e0165835.
[16]RAN L K,CHEN Y,ZHANG Z Z,et al.SIRT6overexpression potentiates apoptosis evasion in hepatocellular carcinoma via BCL2-associated X protein-dependent apoptotic pathway[J].Clin Cancer Res,2016,22(13):3372-3382.
[17]MARQUARDT J U,FISCHER K,BAUS K,et al.Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients[J].Hepatology,2013,58(3):1054-1064.
[18]HAN Z J,LIU L,LIU Y X,et al.Sirtuin SIRT6suppresses cell proliferation through inhibition of Twist1expression in non-small cell lung cancer[J].Int J Clin Exp Pathol,2014,7(8):4774-4781.
[19]ZHU B J,YAN Y J,SHAO B Y,et al.Downregulation of SIRT6is associated with poor prognosis in patients with nonsmall cell lung cancer[J].J Int Med Res,2018,46(4):1517-1527.
[20]CHEN T,SUN Z J,LIU F L,et al.RASSF1Aand SIRT6in non-small cell lung cancer:Relationship with clinical outcome[J].Oncol Lett,2017,14(5):5759-5764.
[21]ZHOU J M,WU A,YU X T,et al.SIRT6inhibits growth of gastric cancer by inhibiting JAK2/STAT3pathway[J].Oncol Rep,2017,38(2):1059-1066.
[22]FUKUDA T,WADA-HIRAIKE O,ODA K,et al.Putative tumor suppression function of SIRT6 in endometrial cancer[J].FEBS Lett,2015,589(17):2274-2281.
[23]ZHANG J,YIN X J,XU C J,et al.The histone deacetylase SIRT6inhibits ovarian cancer cell proliferation via downregulation of Notch 3expression[J].Eur Rev Med Pharmacol Sci,2015,19(5):818-824.
[2]MICHISHITA E,MCCORD R A,BERBER E,et al.SIRT6is a histone H3lysine 9deacetylase that modulates telomeric chromatin[J].Nature,2008,452(7186):492-496.
[3]KAWAHARA T L,MICHISHITA E,ADLER A S,et al.SIRT6links histone H3lysine 9deacetylation to NF-kappaB-dependent gene expression and organismal life span[J].Cell,2009,136(1):62-74.
[4]TANG Y L,ZHOU Y,WANG Y P,et al.SIRT6/NF-kappa B signaling axis in ginsenoside Rg1-delayed hematopoietic stem/progenitor cell senescence[J].Int J Clin Exp Pathol,2015,8(5):5591-5596.
[5]KUGEL S,MOSTOSLAVSKY R.Chromatin and beyond:the multitasking roles for SIRT6[J].Trends Biochem Sci,2014,39(2):72-81.
[6]ZHONG L,D’URSO A,TOIBER D,et al.The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha[J].Cell,2010,140(2):280-293.
[7]CARDUS A,URYGA A K,WALTERS G,et al.SIRT6protects human endothelial cells from DNA damage,telomere dysfunction,and senescence[J].Cardiovasc Res,2013,97(3):571-579.
[8]KANFI Y,PESHTI V,GIL R,et al.SIRT6protects against pathological damage caused by diet-induced obesity[J].Aging Cell,2010,9(2):162-173.
[9]LIAO C Y,KENNEDY B K.Will the real aging Sirtuin please stand up?[J].Cell Res,2012,22(8):1215-1217.
[10]SHUN C T,LIN S K,HONG C Y,et al.Sirtuin 6modulates hypoxia-induced autophagy in nasal polyp fibroblasts via inhibition of glycolysis[J].Am J Rhinol Allergy,2016,30(3):179-185.
[11]SEBASTIN C,ZWAANS B M,SILBERMAN D M,et al.The histone deacetylase SIRT6is a tumor suppressor that controls cancer metabolism[J].Cell,2012,151(6):1185-1199.
[12]GARCIA-PETERSON L M,NDIAYE M A,Singh C K,et al.SIRT6 histone deacetylase functions as a potential oncogene in human melanoma[J].Genes Cancer,2017,8(9/10):701-712.
[13]MING M,HAN W N,ZHAO B Z,et al.SIRT6promotes COX-2expression and acts as an oncogene in skin cancer[J].Cancer Res,2014,74(20):5925-5933.
[14]LIU Y W,XIE Q R,WANG B S,et al.Inhibition of SIRT6in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics[J].Protein Cell,2013,4(9):702-710.
[15]LEE N,RYU H G,KWON J H,et al.SIRT6depletion suppresses tumor growth by promoting cellular senescence induced by DNA damage in HCC[J].PLoS One,2016,11(11):e0165835.
[16]RAN L K,CHEN Y,ZHANG Z Z,et al.SIRT6overexpression potentiates apoptosis evasion in hepatocellular carcinoma via BCL2-associated X protein-dependent apoptotic pathway[J].Clin Cancer Res,2016,22(13):3372-3382.
[17]MARQUARDT J U,FISCHER K,BAUS K,et al.Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients[J].Hepatology,2013,58(3):1054-1064.
[18]HAN Z J,LIU L,LIU Y X,et al.Sirtuin SIRT6suppresses cell proliferation through inhibition of Twist1expression in non-small cell lung cancer[J].Int J Clin Exp Pathol,2014,7(8):4774-4781.
[19]ZHU B J,YAN Y J,SHAO B Y,et al.Downregulation of SIRT6is associated with poor prognosis in patients with nonsmall cell lung cancer[J].J Int Med Res,2018,46(4):1517-1527.
[20]CHEN T,SUN Z J,LIU F L,et al.RASSF1Aand SIRT6in non-small cell lung cancer:Relationship with clinical outcome[J].Oncol Lett,2017,14(5):5759-5764.
[21]ZHOU J M,WU A,YU X T,et al.SIRT6inhibits growth of gastric cancer by inhibiting JAK2/STAT3pathway[J].Oncol Rep,2017,38(2):1059-1066.
[22]FUKUDA T,WADA-HIRAIKE O,ODA K,et al.Putative tumor suppression function of SIRT6 in endometrial cancer[J].FEBS Lett,2015,589(17):2274-2281.
[23]ZHANG J,YIN X J,XU C J,et al.The histone deacetylase SIRT6inhibits ovarian cancer cell proliferation via downregulation of Notch 3expression[J].Eur Rev Med Pharmacol Sci,2015,19(5):818-824.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |