Osborne, C.L.E.; Ogunbiyi, O.; Keshav, S.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA60
Academic Journal
Background and Aims: Phosphoinositide-3-kinose gamma (PI-3-Kγ) is a lipid kinase activated by G-protein coupled receptors (GPCR) to regulate such cellular functions as chemotaxis, cell proliferation and apoptosis. Transgenic mice that lack PI-3-Kγ are immune suppressed and develop colorectal cancer (CRC), and mice lacking the G-protein subunit Gαi2, that may interact with PI-3-Kγ develop ulcerative colitis (UC) and CRC. Patients with UC have a 30% lifetime risk of CRC and UC associated CRC (UC-CRC) develops by o distinct pattern of genetic changes to sporadic CRC. We investigated the expression of PI-3-Kγ in colonic tissue from patients with UC, UC-CRC and CRC. Methods: PI(3)Kγ expression was investigated in normal colon, UC, CRC and UC-CRC by immunohistochemistry and in situ hybridisation. Using RT-PCR and western blotting, PI-3-Kγ expression was determined in normal colonic mucosa, colonic epithelial cells, and the colon cancer cell line (Caco2). Methylation specific PCR was performed on Caco2 cell, sporadic CRC and UC-CRC DNA to determine if silencing of PI-3-Kγ was associated with hypermethylation. Results: PI-3-Kγ expression was demonstrated in leukocytes, colonic epithelial cells and Caco2 cells. All UC specimens expressed PI-3-Kγ protein at higher levels than normal tissue, and expression was lost in the majority of UC-CRC. PI-3-Kγ mRNA was detected in normal tissue, CRC and UC, but was absent in UC-CRC. In Caco2 cells treated with stimulated lymphocyte conditioned medium, expression of PI-3-Kγ was increased, and as the gene is unmethylated in these cells, it is probably upregulated by inflammation, and subsequent loss of expression may be mediated by hypermethylation. Conclusion: Loss of expression of PI(3)Kγ is seen more frequently in UC-CRC than sporadic CRC and our data suggest that it plays a critical role in intestinal epithelial cell function in the context of...


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