Journal
INFLAMMATORY BOWEL DISEASES
Volume 14, Issue 7, Pages 898-907Publisher
OXFORD UNIV PRESS INC
DOI: 10.1002/ibd.20414
Keywords
colitis associated colon cancer; inflammatory bowel disease; animal models of colon cancer; heterotrimeric G-protein signaling
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Funding
- Intramural NIH HHS [Z01 ES101643-05] Funding Source: Medline
- NCI NIH HHS [P30 CA062203] Funding Source: Medline
- NIDDK NIH HHS [K08 DK059816, R21 DK071591, K08 DK59816] Funding Source: Medline
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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.
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