Sa1768 Roles of STAT3 and ZEB1 in E-Cadherin Downregulation and Human Colorectal Cancer EMT

Abstract

Background: One of the most common pathological conditions in the gastrointestinal (GI) tract is increased incidence of malignancy with advancing age. Earlier studies from this laboratory have demonstrated that proliferative activity in the colonic mucosa increases with advancing age, accompanied by a parallel rise in the expression and activation of EGFR. The underlying mechanisms for the age-related rise in GI malignancy, particularly colorectal cancer are poorly understood. Recent evidence suggests that colorectal cancer is driven by self-renewing cancer stem-like cells (CSCs). Earlier, we reported that the age-related increase in adenomas in the colon was associated with increased expression of a number of CSC markers and EGFR in microscopically normal mucosa suggesting a role for CSCs in the development of colorectal neoplasia. We hypothesized that the increase in CSCs and EGFR are related. Methods: Biopsies from colon cancer, adenomatous polyps and normal mucosa from subjects, aged between 40 and 80 years were analyzed for the levels of several markers of CSCs as well as for phospho-EGFR and/or microRNAs by (a) immunohistochemistry, (b) FACS analysis, (c) RT-PCR and/or (d) Western-blot. Results: Analysis of colon cancer specimens revealed a high level of co-expression of total and phospho-EGFR with CD166 (one of the CSC markers). The same phenomenon was also observed in adenomas as well as in normal appearing mucosa of patients with adenomatous polyps. Moreover, co-expression of phospho-EGFR and CD166 in the colonic mucosa was found to be significantly higher in patients with adenomas over 60 years of age than their younger counterparts. In addition, FACS analysis of cells isolated from colonic biopsies of patients with adenomas over 60 years of age revealed a higher proportion of cells expressing CD44+CD166than those below 60 years. This increase was associated with elevated levels of microRNA-21, which is known to regulate the expression of EGFR. Conclusion: Our data suggest that aging leads to an increase in CSCs in the colonic mucosa which is associated with an increase in EGFR expression and this may play a pivotal role in the age-related rise in colorectal cancer.