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 yet been elucidated. Growth factors such as hepatocyte growth factor, which are produced by fibroblasts, have been shown to be important in carcinogenesis and the progression of various human cancers. In the present study, we tested the hypothesis that nonsteroidal anti-inflammatory drugs inhibit hepatocyte growth factor expression through an endogenous prostaglandin-mediated 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 production significantly in a dose- and time-dependent manner. Cholera toxin and 8-bromo cAMP also stimulated hepatocyte growth factor production. Further, prostaglandin E-1 significantly increased cellular cAMP. The prostaglandin EP2 and EP4 receptors were detected by reverse transcription-polymerase chain reaction. Interleukin-1 beta dramatically increased prostaglandin E-2 production and significantly stimulated hepatocyte growth factor synthesis. Interleukin-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 factor by human colonic fibroblasts. Nonsteroidal anti-inflammatory drugs may suppress colon carcinogenesis, in part, through the suppression of hepatocyte growth factor expression by inhibiting endogenous prostaglandin production. (C) 1999 Elsevier Science B.V. All rights reserved.