ROLE OF LIPIDS IN COLON CANCER

花生四烯酸和亚油酸代谢的重要性得到了动物和人类流行病学研究的支持，这些研究表明，阿司匹林和其他非类固醇抗炎药降低了结肠癌的发病率和死亡率，并减少了家族性息肉病患者的息肉。对啮齿动物的实验研究表明，非类固醇抗炎药可以减少致癌物诱导的结肠肿瘤的大小和数量。最近的研究表明，环氧合酶-2在结肠癌和其他肿瘤组织中的表达明显高于邻近正常组织。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。这些酶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。我们正在检测花生四烯酸和亚油酸的代谢，以及人类细胞系中COX-1和-2以及脂氧合酶的表达。丁酸诱导几种人结肠细胞分化和凋亡，并导致COX-2表达和15-脂氧合酶表达降低。在Caco-2细胞中，观察到从前列腺素代谢产物到脂氧合酶代谢产物的戏剧性转变。丁酸盐也可诱导细胞凋亡，但COX抑制剂的加入并不改变这些细胞的凋亡。然而，脂氧合酶抑制剂的加入增强了丁酸盐诱导的细胞凋亡，这表明15-脂氧合酶具有抑制细胞凋亡的作用。未见脂氧合酶的表达。15-脂氧合酶在人结肠组织中有表达，在结直肠肿瘤中的表达增加2-3倍。15-脂氧合酶定位于肠上皮细胞。数据支持组蛋白乙酰化调节人肠上皮细胞15-脂氧合酶-1表达的假说。我们目前正在研究15-脂氧合酶在培养的人结肠和脑细胞中的调节。我们还在开发检测COX-1/-2和15-脂氧合酶过度表达的生物学效应的模型系统。

The importance of arachidonic acid and linoleic acid metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAIDs 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. Recent studies reported that Cox-2 is significantly expressed in colon and other tumors compared to neighboring normal tissue. 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 these enzymes and NSAID treatment is linked to altered apoptosis, cell growth, cell differentiation and angiogenesis. We are examining arachidonic and linoleic acid metabolism, and the expression of Cox-1 and -2, and lipoxygenases in human cell lines. Butyrate-induced differentiation and apoptosis several human colon cells and resulted in a decrease Cox-2 expression and the expression of 15-lipoxygenase. In Caco-2 cells a dramatic shift from prostaglandins metabolites to lipoxygenase metabolites was observed. Butyrate also induces apoptosis, but the addition of Cox inhibitors did not alter the apoptosis in these cells. However, the addition of a lipoxygenase inhibitor enhanced apoptosis induced by butyrate which suggest that 15-lipoxygenase acts to attenuate apoptosis. Expression of lipoxygenase was not observed. Expression of 15-lipoxygenase was observed in human colon tissue with a 2-3 fold increase in expression in colorectal tumors. The 15-lipoxygenase was localized in the intestinal epithelial cell. Data support the hypothesis that histone acetylation regulates the expression of 15-lipoxygenase-1 in human intestinal epithelial cells. We are currently studying the regulation of 15-lipoxygenase in human colorectal and brain cells in culture. We are also developing model systems for examining the biological effects of Cox-1/-2 and 15-lipoxygenase over-expression.