Ota S, Tanaka Y, Bamba H, Kato A, Matsuzaki F
1st Department of Internal Medicine, Saitama Medical Center, Saitama Medical School, Kawagoe City, Japan.
Eur J Pharmacol. 1999 Feb 12;367(1):131-8. doi: 10.1016/s0014-2999(98)00943-1.
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 E2 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 E1 significantly increased cellular cAMP. The prostaglandin EP2 and EP4 receptors were detected by reverse transcription-polymerase chain reaction. Interleukin-1beta dramatically increased prostaglandin E2 production and significantly stimulated hepatocyte growth factor synthesis. Interleukin-1beta induced cyclooxygenase-2 but not cyclooxygenase-1 protein. Indomethacin significantly reduced interleukin-1beta-induced prostaglandin E2 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.
据报道，抑制环氧化酶的非甾体抗炎药可抑制结肠癌的发生。然而，其机制尚未阐明。成纤维细胞产生的生长因子，如肝细胞生长因子，已被证明在各种人类癌症的发生和发展中起重要作用。在本研究中，我们测试了以下假设：非甾体抗炎药通过内源性前列腺素介导的途径抑制培养的人结肠成纤维细胞中肝细胞生长因子的表达。从切除的结肠中获取人结肠成纤维细胞并进行培养。通过酶联免疫吸附测定法测量肝细胞生长因子和前列腺素E2。通过免疫印迹法评估环氧化酶-1和环氧化酶-2蛋白的诱导情况。前列腺素以剂量和时间依赖性方式显著增加肝细胞生长因子的产生。霍乱毒素和8-溴环磷酸腺苷也刺激肝细胞生长因子的产生。此外，前列腺素E1显著增加细胞内的环磷酸腺苷。通过逆转录-聚合酶链反应检测前列腺素EP2和EP4受体。白细胞介素-1β显著增加前列腺素E2的产生并显著刺激肝细胞生长因子的合成。白细胞介素-1β诱导环氧化酶-2但不诱导环氧化酶-1蛋白。吲哚美辛显著降低白细胞介素-1β诱导的前列腺素E2释放和肝细胞生长因子的产生。这些结果表明，前列腺素是人类结肠成纤维细胞产生肝细胞生长因子的一个因素。非甾体抗炎药可能部分通过抑制内源性前列腺素的产生来抑制肝细胞生长因子的表达，从而抑制结肠癌的发生。
