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Ets2 regulates colonic stem cells and sensitivity to tumorigenesis


Colorectal cancer is one of the leading causes of cancer related death in the U.S. Approximately 150,000 cases and 50,000 deaths due to the disease occurred last year. Alterations in the Wnt signaling pathway (Wnt, APC, [Beta] -catentin) are common in colorectal cancer. As the disease progresses mutations in K-ras, p53 and TGF-[alpha] also arise. Given the role of Wnt signaling in the maintenance of the intestinal epithelium, colorectal cancer is likely due to a misregulation of normal developmental pathways. Ets2, a member of the Ets family of transcription factors, has been identified as a Wnt target in colorectal cancer cells and in intestinal stem cells. Ets2 has also been identified as a tumor repressor of APCMin intestinal tumorigenesis in the mouse equivalent of trisomy 21. In contrast to a tumor repressive effect, previous studies in this lab have shown that Ets2 has a tumor supportive function through the tumor microenvironment in transgenic mouse mammary tumor models. This apparent paradox can be resolved if Ets2 regulates an intestinal specific tumor suppressive mechanism. Ets2 has been previously shown to activate transcription of the caudal-type homeobox 2 gene (Cdx2) by through a conserved distal region of its promoter in both trophoblast stem cells and in colon cancer cells. Since Cdx2 functions as a tumor suppressor in the distal colon, the cell autonomous role of Ets2 was examined in postnatal colon development and in suppression of tumorigenesis. Using a conditional allele of Ets2 (Ets2flox), and Cre-mediated deletion within the intestinal epithelium, the cell autonomous role of Ets2 was examined. Ets2 deficient cells had a selective advantage in populating distal colon crypts. Furthermore, Ets2 deficient crypts increased in number during the developmental period in which crypt fission rates peak. Consistent with this observation, Ets2 deficient crypts underwent fission more frequently than crypts retaining Ets2. This data suggest that Ets2 deficient stem cells have a selective advantage due to an increase in stem cell proliferation. An increase in stem cell number or proliferation may lead to an increase in tumorigenesis since stem cells are the cell of origin of intestinal tumors in mouse. To test this hypothesis, the colitis associated cancer (CAC) model was used. Tumor multiplicity was increased significantly is Ets2flox/flox VillinCre+ versus Ets2flox/+ VillinCre+ or Ets2flox/flox V-Cre- mice. Tumor size did not differ significantly between the three genotypes. These data support the conclusion that Ets2 acts as a cell autonomous tumor suppressor of intestinal tumorigenesis by inhibiting tumor initiation. To determine if Ras/MAPK activation of Ets2 is required for its tumor suppressive activity, mice carrying a hypomorphic allele defective in Ras/MAPK activation (Ets2A72) were subjected to the colitis associated cancer model. Ets2A72/A72 mice developed twice as many tumors as wild-type animals. Furthermore, induction of acute colitis revealed no significant differences in clinical or histological scoring. In addition, Ets2A72 mice subjected to multiple AOM injections in the absence of colitis had an increase in tumor incidence and multiplicity. These data indicate that activation of Ets2 by phoshorylation of Thr-72 is important for inhibiting tumor development and this affect is not likely mediated by inflammation. To gain insight into how Ets2 is regulated in human colon cancer cells, studies were conducted using the Caco2 human colon cancer cell line. Caco2 cells recapitulate many aspects of differentiation of intestinal epithelial cells. Increased Ets2 protein expression was found to be associated with a more differentiated state of these cells. The increase in protein levels was not due to an increase in Ets2 mRNA, suggesting that Ets2 protein levels are regulated post- transcriptionally in the Caco2 d

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