Role Of Lipids In Colon, Breast, And Other Cancers

花生四烯酸（AA）和亚油酸（LA）代谢的重要性得到动物和人类流行病学研究的支持，这些研究表明阿司匹林和其他非甾体抗炎药能够抑制Cox活性，降低家族性息肉病患者结肠癌的发病率和死亡率，减少息肉。对啮齿动物的实验研究表明，非甾体抗炎药可以减少致癌物诱导的结肠肿瘤的大小和数量。前列腺素和其他脂质在结肠癌和其他癌症的发生和发展中起着重要作用，但其机制尚不清楚。Cox和LOX的表达和非甾体抗炎药治疗与细胞凋亡、细胞生长、细胞分化和血管生成的改变有关。我们正在研究花生四烯酸和亚油酸的代谢，以及Cox-1和-2和脂氧合酶在人类细胞系中的表达。除Cox-2外，15-脂氧合酶在结直肠和前列腺肿瘤中表达较高。数据支持组蛋白乙酰化调节人肠上皮细胞15-脂氧合酶-1表达的假设。在前列腺细胞中15-LOX-1具有致瘤作用，而在结直肠组织中脂氧合酶具有抗致瘤作用。这些脂氧合酶及其代谢产物改变了生长因子信号通路和15-HETE和13-HODE， AA和LA的代谢产物具有相反的生物学反应。此外，实验室正在研究Cox-1和Cox-2在细胞中的表达和调控。一个意想不到的发现是HDAC抑制剂在脑细胞中上调Cox-1，而不是上调15-LOX-1。我们的计划是继续研究15-LOX和Cox-1 & 2的调控，并关注这些酶如何促进癌症的发展。

The importance of arachidonic acid (AA) and linoleic acid (LA) metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAIDs that inhibit Cox activity, reduce the incidence and mortality of colon cancer and reduce polyps in patients with familial polyposis. Experimental studies with rodents indicate that NSAIDs reduce both the size and number of colon tumors induced by carcinogens. Prostaglandins and other lipids play a major role in the development and progression of colon and other cancers but the mechanism is not clear. The expression of Cox and LOX and NSAID treatment is linked to altered apoptosis, cell growth, cell differentiation and angiogenesis. We are examining arachidonic acid and linoleic acid metabolism, and the expression of Cox-1 and -2, and lipoxygenases in human cell lines. In addition to Cox-2, the expression of 15-lipoxygenase is higher in colorectal and prostate tumors. Data support the hypothesis that histone acetylation regulates the expression of 15-lipoxygenase-1 in human intestinal epithelial cells. In prostate cells 15-LOX-1 has a pro-tumorigenic effect while in colorectal tissue the lipoxygenase has an anti-tumorigenic effect. These lipoxygenases and their metabolites alter growth factor signaling pathways and 15-HETE and 13-HODE, the metabolites of AA and LA have opposing biological responses. In addition, the laboratory is studying the expression and regulation of Cox-1 and Cox-2 in cells. One unexpected finding is the up-regulation of Cox-1 but not 15-LOX-1 by HDAC inhibitors in brain cells. Our plans are to continue to investigate the regulation of 15-LOX and Cox-1 &-2 and to focus on how these enzyme contribute to the development of cancers.