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甾体抗炎药可以降低家族性息肉病患者结肠癌的发病率和死亡率，并减少息肉的发生。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。最近的研究报道，Cox-2在结肠和其他肿瘤中与邻近的正常组织相比显著表达。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。丁酸盐诱导人结肠细胞分化和凋亡，降低Cox-2和15-脂氧合酶的表达。在Caco-2细胞中观察到从前列腺素代谢物到脂氧合酶代谢物的戏剧性转变。丁酸盐也能诱导细胞凋亡，但添加Cox抑制剂对细胞凋亡无明显影响。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-脂氧合酶有减弱细胞凋亡的作用。脂氧合酶未见表达。15-脂氧合酶在人结肠组织中表达，在结直肠肿瘤中表达量增加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表达的假设。我们目前正在研究15-脂氧合酶在人结肠细胞和培养的脑细胞中的调节作用。我们也在开发模型系统来检测Cox-1/ 2和15-脂氧合酶过表达的生物学效应。

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.