Expression Of T Cell Factor-4 In Human Colorectal Carcinomas And Adenomas

Background and Aim: Colorectal carcinoma is one of the most commonforms of cancer in digestive system. Up to now, diagnosis in the early stageand radical cure of this disease barge up against various difficulties. And itsfive-year Survival remains around 50%. However, the cause and mechanismof human colorectal carcinoma are still not clearly elucidated. Recently,Alteration of APC/β-Catenin/Tcf pathway, also known as canonical Wntsignaling pathway, has been implicated in human colorectal tumorigenesis.Regulation of cell growth and differentiation by Wnt signaling pathwayis fulfilled via transcription of various target genes activated by Tcfs (T cellfactors). Without Wnt signals, CBP (CREB-binding protein) or CtBP(C-terminal bind protein) as a repressor binds to Tcf-4, and then blocks thetranscription of downstream target genes. While activated by Wnt signals,β-catenin migrates into nucleus and competitively binds to Tcf-4, activatingthe transcription of target genes. Thus, Tcfs are considered as molecularswitches which play an important role in carcinogenesis.Tcf-4 is related to the colorectal neoplasm, because it is the only one of Tcf family members which is highly expressed in colonic epithelia. Up tonow, most studies of Tcf-4 were laid emphasis on mutations of Tcf-4 andmechanisms of regulation of Tcf-4 transcriptional activity. And most of theirconclusions were drawn from in vitro studies. Does Tcf-4 level vary indifferent stages of tumorigenesis? Is there any relationship between Tcf-4expression and patients' clinicopathologic characters? Do Tcf-4 isoformsdetected in in vitro studies exist in human colorectal tissue? These issuesabout Tcf-4 are not clearly clarified yet. Previous study of our groupidentified up-regulation of Tcf-4 mRNA in human colorectal carcinomas. Thepresent study was designed to examine the expression of Tcf-4 protein inhuman colorectal carcinomas, adenomas and paracancerous tissues byimmunohistochemical staining and Western blotting. The aim of this study isto clarify whether Tcf-4 level varies in different colorectal tissues and toinvestigate the correlation between Tcf-4 expression and patients'clinicopathological features.Methods: Specimens of sixty primary colorectal tumors, including 29sporadic colorectal adenomas and 31 colorectal carcinomas were detected forTcf-4 expression by immunohistochemistry and Western blotting. Bothmanual scoring approach and computer-assisted image analysis were utilizedfor semi-quantitative analysis of immunohistochemical staining.Results:1. The level of Tcf-4 protein in 31 colorectal carcinomas and 29colorectal adenomas was significantly higher than that in normal colorectalmucosae (P=0.007 and P=0.003 respectively). The expression of Tcf-4protein in adenomas was not statistically different from that in carcinomas (P=0.783).2. Tcf-4 expression was significantly associated with Dukes Staging(P=0.005). And level of Tcf-4 protein in adenomas is up-regulated with theincreasing of dysplasia grade (P=0.019).3. One isoform of Tcf-4 around 66kD was detected by Westernimmunoblotting.Conclusions:1. Over-expression of Tcf-4 may participate in human colorectaltumorigenesis.2. Tcf-4 expression was significantly associated with Dukes Staging. Itsuggests that over-expression of Tcf-4 may play a role in invasion andmetastasis of colorectal carcinoma.