Nonsteroidal anti-inflammatory drugs may prevent colon cancer through suppression of hepatocyte growth factor expression

Nonsteroidal anti-inflammatory drugs which inhibit cyclooxygenase have been reported to suppress colon carcinogenesis. However the mechanism has not y et been elucidated. Growth factors such as hepatocyte growth factor, which are produced by fibroblasts, have been shown to be important in carcinogene sis and the progression of various human cancers. In the present study, we tested the hypothesis that nonsteroidal anti-inflammatory drugs inhibit hep atocyte growth factor expression through an endogenous prostaglandin-mediat ed pathway in cultured human colonic fibroblasts. Human colonic fibroblasts were obtained from a resected colon and cultured. Hepatocyte growth factor and prostaglandin E-2 were measured by enzyme-linked immunosorbent assay. Induction of cyclooxygenase-1 and cyclooxygenase-2 protein was estimated by immunoblotting. Prostaglandins increased hepatocyte growth factor producti on significantly in a dose- and time-dependent manner. Cholera toxin and 8- bromo cAMP also stimulated hepatocyte growth factor production. Further, pr ostaglandin E-1 significantly increased cellular cAMP. The prostaglandin EP 2 and EP4 receptors were detected by reverse transcription-polymerase chain reaction. Interleukin-1 beta dramatically increased prostaglandin E-2 prod uction and significantly stimulated hepatocyte growth factor synthesis. Int erleukin-1 beta induced cyclooxygenase-2 but not cyclooxygenase-l protein. Indomethacin significantly reduced interleukin-1 beta-induced prostagrandin E-2 release and hepatocyte growth factor production. These results suggest that prostaglandin is a factor for the production of hepatocyte growth fac tor by human colonic fibroblasts. Nonsteroidal anti-inflammatory drugs may suppress colon carcinogenesis, in part, through the suppression of hepatocy te growth factor expression by inhibiting endogenous prostaglandin producti on. (C) 1999 Elsevier Science B.V. All rights reserved.