The Expression Of Tensin 4 In Human Sporadic Colorectal Carcinoma And Its Epigenetic Mechanism And The Clinical Significance

Background:Colorectal cancer(CRC)is one of the most common types of malignant tumors with a high motality rate.It's necessary to find out reliable molecular biomarkers to predict the prognosis of this tumor.Objeetive:To identify whether TNS4 protein could be used as a prognostic marker in patients with CRC.Methods:The expression of TNS4 protein in 139 CRC tissues and their paired tissue samples,as well as in 27 adenoma tissues were detected by immunohistochemical staining(IHS)and western blot,and its expression was further confirmed by RT-PCR. The expression of TNS4 in the colorectal cancer cell lines was also detected by western blot and RT-PCR.The methylation status of the TNS4 promoter was examined by bisulphite sequencing PCR(BSP)in cell lines and was correlated with gene expression. The methylation of TNS4 promoter was tested by methylation specific PCR(MSP)in 20 CRC tissues.All the patients were followed up,and their clinicalpathological characteristics were correlated with the TNS4 espression and analyzed with univariate and multivariate statistic analysis.P value(?)0.05 was considered as significance.Results:The expression rate of TNS4 protein in the sporadic CRC(65.5%)was significantly higher than the paired control group(5.3%,P=2.15×10-14)and the adenoma group(37%,P=0.009).The expression of TNS4 mRNA in CRC tissue was also significantly higher than the control group(P=8.30×10-7).The low methylation state of TNS4 promoter region-136-+49 detected by BSP was significantly correlated with the expression of TNS4 protein expression in colorectal cancer cell lines, whereas both condition of methylation and un-methylation existed in tissues.The expression of TNS4 protein in CRC tissue was significantly associated with the clinical stage,the expression rate elevated fromⅠstage toⅣstage tumors(Chi-squire P=5.26×10-5,Logistic regression P=4.38×10-5).Those patients who had lyphnode metastastis pre-surgery had a higher exptession(81%)than those no lyphnode metastasis(53%) (Both Chi—squire and Logistic regression,P=0.001).Also the expression of TNS4 protein in those who had distant metastasis pre-surgery was higher than the expression in thos who had no lyphnode metastasis(P was 0.001 and 0.004 for Chi-squire and Logistic regression respectively). The distant metastatic risk after surgery in the TNS4 espression group was 14.9 times than the unexpression group (P=0.001).The expression of TNS4 protein could lead to a decrease of the survival rate (P=O.007),and Cox regression revealed that TNS4 protein might be an independent predictor of the prognosis of CRC patients,although there was no obviouse statistical significance(P=0.185).Conclusions:The expression of TNS4 protein and mRNA were detected in CRC tissues, and one of the epigenetic mechanisms of its expression in cell lines was the low methylation state of TNS4 promoter region.The expression of TNS4 protein was notably correlated with the metastasis of lyphnode and the distant metastasis,and also had a negative correlation with the survival of CRC patients.TNS4 protein might be a new prognostic bio-marker for CRC patients.