Murray Nicole R, Weems Capella, Chen Lu, Leon Jessica, Yu Wangsheng, Davidson Laurie A, Jamieson Lee, Chapkin Robert S, Thompson E Aubrey, Fields Alan P
Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1048, USA.
J Cell Biol. 2002 Jun 10;157(6):915-20. doi: 10.1083/jcb.200201127.
Increasing evidence demonstrates that protein kinase C betaII (PKCbetaII) promotes colon carcinogenesis. We previously reported that colonic PKCbetaII is induced during colon carcinogenesis in rodents and humans, and that elevated expression of PKCbetaII in the colon of transgenic mice enhances colon carcinogenesis. Here, we demonstrate that PKCbetaII represses transforming growth factor beta receptor type II (TGFbetaRII) expression and reduces sensitivity to TGF-beta-mediated growth inhibition in intestinal epithelial cells. Transgenic PKCbetaII mice exhibit hyperproliferation, enhanced colon carcinogenesis, and marked repression of TGFbetaRII expression. Chemopreventive dietary omega-3 fatty acids inhibit colonic PKCbetaII activity in vivo and block PKCbetaII-mediated hyperproliferation, enhanced carcinogenesis, and repression of TGFbetaRII expression in the colonic epithelium of transgenic PKCbetaII mice. These data indicate that dietary omega-3 fatty acids prevent colon cancer, at least in part, through inhibition of colonic PKCbetaII signaling and restoration of TGF-beta responsiveness.
越来越多的证据表明，蛋白激酶CβII（PKCβII）促进结肠癌的发生。我们之前报道过，啮齿动物和人类结肠癌发生过程中结肠PKCβII会被诱导，并且转基因小鼠结肠中PKCβII的高表达会增强结肠癌的发生。在此，我们证明PKCβII抑制II型转化生长因子β受体（TGFβRII）的表达，并降低肠道上皮细胞对TGF-β介导的生长抑制的敏感性。转基因PKCβII小鼠表现出过度增殖、结肠癌发生增强以及TGFβRII表达明显受抑制。具有化学预防作用的膳食ω-3脂肪酸在体内抑制结肠PKCβII活性，并阻断PKCβII介导的转基因PKCβII小鼠结肠上皮过度增殖、致癌作用增强以及TGFβRII表达受抑制。这些数据表明，膳食ω-3脂肪酸至少部分通过抑制结肠PKCβII信号传导和恢复TGF-β反应性来预防结肠癌。
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