Role for epithelial dysregulation in early-onset colitis-associated colon cancer in Gi2-alpha-/- mice.
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.
Edwards
Robert A
RA
Department of Pathology, University of California, Irvine, Irvine, California 92697-4800, USA. redwards@uci.edu
Wang
Kehui
K
Davis
Jennifer S
JS
Birnbaumer
Lutz
L
D000818:Animals; D017209:Apoptosis; D016718:Arachidonic Acid / Q000378:metabolism; D045744:Cell Line, Tumor; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology / Q000503:physiopathology*; D004848:Epithelium / Q000473:pathology / Q000502:physiology; D044385:GTP-Binding Protein alpha Subunits / Q000172:deficiency* / Q000502:physiology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications; D051379:Mice
D044385:GTP-Binding Protein alpha Subunits; D016718:Arachidonic Acid