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Robert A. Edwards, Kehui Wang, Jennifer S. Davis, Lutz Birnbaumer, Role for epithelial dysregulation in early-onset colitis-associated colon cancer in Gi2-alpha−/− mice, Inflammatory Bowel Diseases, Volume 14, Issue 7, 1 July 2008, Pages 898–907, https://doi.org/10.1002/ibd.20414
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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.
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.
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.
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.