To Explore The Molecular Mechanism Of The ¦Â-catenin/tcf Pathway Is Abnormally Activated In Tumors

β-catenin/TCF pathway plays important roles in regulating cellular differentiation and proliferation during embryonic development and leads to tumor formation when aberrantly activated. Although compelling evidence has indicated a crucial role for signaling by β-catenin/TCF in the tumorigenesis of ESCC (esophageal squamous cell carcinomas) and ovarian serous adenocarcinoma, genetic mutations of APC (adenomatous polyposis coli), CTNNB1 (β-catenin) or Axin are rarely found in these tumors. Therefore, additional mechanisms can be used to upregulate β-catenin levels. Previous studies have shown that FRAT1 (frequently rearranged in advanced T-cell lymphomas 1) and EB1 (end-binding protein 1) are strikingly overexpressed in some human cancer cell lines. Furthermore, FRAT1 is a positive regulator of the β-catenin/TCF pathway and EB1 has the potential to activate this pathway by affecting APC tumor suppressor function. However, whereas FRAT1 and EB1 are candidates for accumulation of cytoplamsic β-catenin, little is known with regard to the molecular relationship between FRAT1 or EB1 and p-catenin in human cancers.In this study, FRAT1 or EB1 cDNA was cloned and transfected into ESCC cell lines, HEK293 and NIH 3T3 cells (a mouse fibroblast cell line), and the effects of FRAT1 or EB1 overexpression on cellular phenotypes and transcriptional activity of β-catenin/TCF were analyzed. RNAi (RNA interference) was also used to determine the functions of FRAT1 and EB1. In situ hybridization and immunohistochemical analysis were performed to identify the level of FRAT1 mRNA or EB1 expression and the localization of β-catenin in surgical specimens of ESCC or ovarian cancer tissue microarrays respectively.We demonstrate that FRAT1 or EB1 is overexpressed in ESCC and aberrant activation of β-catenin/TCF pathway in esophageal cancer appears to be due to upstream events such as FRAT1 overexpression or elevated EB1 expression. Also, we suggest that β-catenin/TCF pathway may be aberrantly activated through FRAT1 overexpression in ovarian serous adenocarcinoma.Analysis of freshly resected ESCC specimens showed that FRAT1 was overexpressed in approximately 74% of tumor samples compared to matched normal ones. We found that...