大肠癌组织中PIK3CA和PIK3CB的表达及意义
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摘要
目的观察癌基因PIK3CA、PIK3CB在大肠癌组织中的表达及其相互关系,并分析PIK3CA和PIK3CB的表达对大肠癌患者预后的影响。方法采用免疫组化EnVision法染色并结合图像进行分析,探讨PIK3CA和PIK3CB在大肠癌组织及正常大肠黏膜组织中的表达;应用RT-PCR和Western blot技术分别检测PIK3CA mRNA和PIK3CB mRNA及其相应蛋白的表达;回访125例大肠癌术后患者,生存分析用Kaplan-Meier法,生存曲线用Log-Rank检验。结果在300例大肠癌蜡块组织及正常黏膜组织中,PIK3CA表达的平均光密度值分别为:10.087 9±2.148 7、6.937 6±2.065 3,PIK3CB表达的平均光密度值分别为:15.870 6±2.877 7、8.693 2±2.442 4。PIK3CA和PIK3CB在大肠癌组织中的表达具有相关性(r=0.68,P<0.05);RT-PCR检测结果显示,与正常大肠黏膜组织相比,大肠癌组织中PIK3CA mRNA和PIK3CB mRNA的表达水平均明显升高,且二者表达结果呈正相关(r=0.74,P<0.05);Western blot法检测发现PIK3CA和PIK3CB蛋白表达水平同样升高,二者表达结果呈正相关(r=0.71,P<0.05);生存分析显示PIK3CA和PIK3CB高表达与患者死亡风险具有明显相关性。结论 PIK3CA和PIK3CB在大肠癌组织中高表达,与正常黏膜组织中的表达相比差异较明显,且PIK3CA和PIK3CB在大肠癌的发生、发展中具有协同作用,PIK3CA、PIK3CB高表达亦是大肠癌患者预后相关的因素之一。检测大肠癌患者PIK3CA和PIK3CB的表达对于控制大肠癌的进展、确定大肠癌的靶点治疗及判断预后具有重要意义。
Purpose To investigate the expression and significance of PIK3CA and PIK3CB in human colorectal carcinoma,and study the correlation between expression of PIK3CA and PIK3CB and the prognosis of colorectal carcinoma.Methods Immunohistochemical and image analysis were to detect the expression of PIK3CA and PIK3CB in tumor tissue and normal colorectal mucosa tissue.RT-PCR and Western blot were employed to detect the expression of PIK3CA and PIK3CB.After the follow-up results were obtained for 125 colorectal cancer patients,survival analysis was used by Kaplan-Meier methods and survival curve was examined by Long-Rank test.Results Of 300 cases of colorectal carcinoma and normal colorectal mucosa,average value of light density of PIK3CA was 10.087 9±2.148 7 and 6.937 6±2.065 3,PIK3CB was 15.870 6±2.877 7 and 8.693 2±2.442 4 respectively.The expression of PIK3CA and PIK3CB were a linear correlation and the correlation coefficient(r) of them was 0.68.There was a positive correlation between the expression of PIK3CA and PIK3CB in colorectal carcinoma.The expression of PIK3CA and PIK3CB mRNA and protein in tumor tissue were higher than those in normal colorectal mucosa tissue.There was a positive correlation between the expression of PIK3CA and PIK3CB in tumor tissue,and the correlation coefficient(r)of them were 0.74 and 0.71 respectively.Kaplan-Meier survival analysis showed that the patients with high PIK3CA expression and high PIK3CB expression in the tumors had a lower survival rate(P<0.05).Conclusion The results suggest that PIK3CA and PIK3CB have a coordinated effect in the carcinogenesis and development in human colorectal carcinoma,and further to supply experimental and theoretical guides for controlling the progression of colorectal carcinoma,determining the therapeutic target for colorectal carcinoma and evulating the prognosis of colorectal carcinomas.
Purpose To investigate the expression and significance of PIK3CA and PIK3CB in human colorectal carcinoma,and study the correlation between expression of PIK3CA and PIK3CB and the prognosis of colorectal carcinoma.Methods Immunohistochemical and image analysis were to detect the expression of PIK3CA and PIK3CB in tumor tissue and normal colorectal mucosa tissue.RT-PCR and Western blot were employed to detect the expression of PIK3CA and PIK3CB.After the follow-up results were obtained for 125 colorectal cancer patients,survival analysis was used by Kaplan-Meier methods and survival curve was examined by Long-Rank test.Results Of 300 cases of colorectal carcinoma and normal colorectal mucosa,average value of light density of PIK3CA was 10.087 9±2.148 7 and 6.937 6±2.065 3,PIK3CB was 15.870 6±2.877 7 and 8.693 2±2.442 4 respectively.The expression of PIK3CA and PIK3CB were a linear correlation and the correlation coefficient(r) of them was 0.68.There was a positive correlation between the expression of PIK3CA and PIK3CB in colorectal carcinoma.The expression of PIK3CA and PIK3CB mRNA and protein in tumor tissue were higher than those in normal colorectal mucosa tissue.There was a positive correlation between the expression of PIK3CA and PIK3CB in tumor tissue,and the correlation coefficient(r)of them were 0.74 and 0.71 respectively.Kaplan-Meier survival analysis showed that the patients with high PIK3CA expression and high PIK3CB expression in the tumors had a lower survival rate(P<0.05).Conclusion The results suggest that PIK3CA and PIK3CB have a coordinated effect in the carcinogenesis and development in human colorectal carcinoma,and further to supply experimental and theoretical guides for controlling the progression of colorectal carcinoma,determining the therapeutic target for colorectal carcinoma and evulating the prognosis of colorectal carcinomas.
引文
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[17]Tang M K,Zhou H Y,Yam J W,et al.c-Met over expressioncontributes to the acquired apoptotic resistance of nonadherent o-varian cancers cells through a cross talk mediated by phosphatidyli-nositol3-kinase and extracellularsignal-regulated kinase1/2[J].Neoplasia,2010,12(2):128-38.
[18]Jost C A,Marin M C,Daelin W G.p73 is a human p53-relatedprotein that can induce apoptosis[J].Nature,1997,389(1)191-9.
[2]Izycka-Swieszewska E,Brzeskwiniewicz M,Wozniak A,et al.EGFR,PIK3CA and PTEN gene status and their protein productexpression in neuroblastic tumours[J].Folia Neuro Pathol,2010,48(4):238-45.
[3]Dbouk H A,Backer J M.A beta version of life:p110βtakes cen-ter stage[J].Oncotarget,2010,1(8):729-33.
[4]Carnero A,Blanco-Aparicio C,Renner O,et al.The PTEN/PI3K/AKT signalling pathway in cancer,therapeutic implications[J].Curr Cancer Drug Targets,2008,8(3):187-98.
[5]Yuan T L,Cantley L C.PI3K pathway alterations in cancer:varia-tions on a theme[J].Oncogene,2008,27(41):5497-510.
[6]Xing M.Recent advances in molecular biology of thyroid cancerand their clinical implications[J].Otolaryngol Clin North Am,2008,41(6):1135-46.
[7]Zhao L,Vogt P K.Helical domain and kinase domain mutations inp110 of Phosphate-dylinositol 3-kinase induce gain of function bydifferert mechanisms[J].Proc Natl Acad Sci USA,2008,105(7):2652-7.
[8]Hutti J E,Pfefferle A D,Russell S C,et al.Oncogenic PI3K mu-tations lead to NF-κB-dependent cytokine expression followinggrowth factor deprivation[J].Cancer Res,2012,72(13):3260-9.
[9]Janku F,Wheler J J,Westin S N,et al.PI3K/AKT/mTOR in-hibitors in patients with breast and gynecologic malignancies harbo-ring PIK3CA mutations[J].J Clin Oncol,2012,30(8):777-82.
[10]Agell L,Hernández S,Salido M,et al.PI3K signaling pathway isactivated by PIK3CA mRNA overexpression and copy gain in pros-tate tumors,but PIK3CA,BRAF,KRAS and AKT1 mutations areinfrequent events[J].Mod Pathol,2011,24(3):443-52.
[11]Wang L E,Ma H,Hale K S,et al.Roles of genetic variants inthe PI3K and RAS/RAF pathways in susceptibility to endometrialcancer and clinical outcomes[J].J Cancer Res Clin Oncol,2012,138(3):377-85.
[12]李扬扬,吴淑华.PIK3CA蛋白在大肠癌变过程中的表达及临床意义[J].滨州医学院学报,2010,33(1):5-8.
[13]高向前,吴淑华.结直肠癌组织中PI3KCB蛋白表达及其与多药耐药基因产物的相关性[J].山东医药,2012,14(52):7-9.
[14]高向前,吴淑华.结直肠癌与不同上皮内瘤变腺瘤中PI3Kp110β的表达及临床意义[J].临床与实验病理学杂志,2012,28(5):518-21.
[15]Samuels Y,Velculescu V E.Oncogenic mutations of PIK3CA inhuman cancers[J].Cell Cycle,2004,3(10):1221-4.
[16]Ogino S,Nosho K,Kirkner G J,et al.PIK3CA mutation is asso-ciated with poor prognosis among patients with curatively resectedcolon cancer[J].J Clin Oncol,2009,27(9):1477-84.
[17]Tang M K,Zhou H Y,Yam J W,et al.c-Met over expressioncontributes to the acquired apoptotic resistance of nonadherent o-varian cancers cells through a cross talk mediated by phosphatidyli-nositol3-kinase and extracellularsignal-regulated kinase1/2[J].Neoplasia,2010,12(2):128-38.
[18]Jost C A,Marin M C,Daelin W G.p73 is a human p53-relatedprotein that can induce apoptosis[J].Nature,1997,389(1)191-9.