ROLE OF LIPIDS IN COLON CANCER

花生四烯酸和亚油酸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NSAID可降低结肠癌的发病率和死亡率，并减少家族性息肉病患者的息肉。对啮齿动物的实验研究表明，非甾体类抗炎药可减少致癌物诱发的结肠肿瘤的大小和数量。最近的研究报道，与邻近的正常组织相比，考克斯-2在结肠和其他肿瘤中显著表达。前列腺素和其他脂质在结肠癌和其他癌症的发展和进展中起着重要作用，但其机制尚不清楚。这些酶的表达和NSAID治疗与改变的细胞凋亡、细胞生长、细胞分化和血管生成有关。我们正在研究花生四烯酸和亚油酸的代谢，以及考克斯-1和-2，和脂氧合酶在人类细胞系中的表达。丁酸诱导人结肠癌细胞分化和凋亡，导致考克斯-2表达和15-脂氧合酶表达下降。在Caco-2细胞中，观察到从木兰素代谢物到脂氧合酶代谢物的显著转变。丁酸也诱导凋亡，但添加考克斯抑制剂并没有改变这些细胞的凋亡。然而，添加脂氧合酶抑制剂增强丁酸盐诱导的细胞凋亡，这表明15-脂氧合酶起减弱细胞凋亡的作用。未观察到脂氧合酶的表达。在人结肠组织中观察到15-脂氧合酶的表达，在结肠直肠肿瘤中表达增加2 - 3倍。15-脂氧合酶定位于肠上皮细胞。数据支持的假设，组蛋白乙酰化调节15-脂氧合酶-1在人类肠上皮细胞的表达。 我们目前正在研究15-脂氧合酶在人类结肠直肠和脑细胞培养的调节。我们也正在开发模型系统，用于检查考克斯-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.