Open AccessRole for epithelial dysregulation in early‐onset colitis‐associated colon cancer in Gi2‐alpha−/− mice
Author(s) -
Edwards Robert A.,
Wang Kehui,
Davis Jennifer S.,
Birnbaumer Lutz
Publication year - 2008
Publication title -
inflammatory bowel diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.932
H-Index - 146
eISSN - 1536-4844
pISSN - 1078-0998
DOI - 10.1002/ibd.20414
Subject(s) - colorectal cancer , cancer research , inflammatory bowel disease , colitis , alpha (finance) , medicine , familial adenomatous polyposis , apoptosis , cancer , biology , pathology , disease , construct validity , biochemistry , nursing , patient satisfaction
Background: Inflammatory bowel disease (IBD) is a risk factor for developing colorectal cancer but the mechanisms are poorly characterized. Mice lacking the G‐protein alpha subunit Gi2‐alpha spontaneously develop colitis and colon cancer with high penetrance. Compared to canonical Wnt/APC signaling‐based animal models of colon cancer, the tumors in Gi2‐alpha−/− mice more closely recapitulate the features of IBD‐associated cancers seen in humans. They are predominantly right‐sided, multifocal, mucinous, and arise from areas of flat dysplasia. Methods: In evaluating the potential contribution of epithelial Gi2‐alpha signaling to this phenotype, we found that Gi2‐alpha−/− colonic epithelium is hyperproliferative even before the onset of colitis, and resistant to the induction of apoptosis. We generated colon cancer cell lines overexpressing dominant‐negative Gi2‐alpha. Results: Like other cells lacking Gi2‐alpha, these cells release less arachidonic acid, an important antiinflammatory and epithelial growth regulator. They are also hyperproliferative and resistant to camptothecin‐induced apoptosis and caspase‐3 activation. Conclusions: The colitis‐associated cancers in Gi2‐alpha−/− mice appear very similar to those seen in human IBD patients, and Gi2‐alpha is a direct negative regulator of colonic epithelial cell growth. (Inflamm Bowel Dis 2008)