Algamas-Dimantov Anna, Yehuda-Shnaidman Einav, Hertz Rachel, Peri Irena, Bar-Tana Jacob, Schwartz Betty
Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel.
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
Oncotarget. 2014 Oct 30;5(20):9851-63. doi: 10.18632/oncotarget.2453.
The global obesity / diabetes epidemic has resulted in robust increase in the incidence of colorectal cancer (CRC). Epidemiological, animal and human studies have indicated efficacy of (n-3) PUFA in chemoprevention of sporadic and genetic-driven CRC. However, diabetes-promoted CRC presents a treatment challenge that surpasses that of sporadic CRC. This report analyzes the efficacy of (n-3) PUFA generated by the fat-1 transgene that encodes an (n-6) to (n-3) PUFA desaturase, and of synthetic (n-3) PUFA mimetic (MEDICA analog), to suppress CRC development in carcinogen-induced diabetes-promoted animal model. Carcinogen-induced CRC is shown here to be promoted by the diabetes context, in terms of increased aberrant crypt foci (ACF) load, cell proliferation and epithelial dedifferentiation, being accompanied by increase in the expression of HNF4α, β-catenin, and β-catenin-responsive genes. Incorporating the fat-1 transgene in the diabetes context, or oral MEDICA treatment, resulted in ameliorating the diabetic phenotype and in abrogating CRC, with decrease in ACF load, cell proliferation and the expression of HNF-4α, β-catenin, and β-catenin-responsive genes. The specificity of (n-3) PUFA in abrogating CRC development, as contrasted with enhancing CRC by (n-6) PUFA, was similarly verified in CRC cell lines. These findings may indicate prospective therapeutic potential of (n-3) PUFA or MEDICA in the management of CRC, in particular diabetes-promoted CRC.
全球肥胖/糖尿病流行导致结直肠癌（CRC）发病率强劲上升。流行病学、动物和人体研究表明，（n-3）多不饱和脂肪酸（PUFA）在散发性和基因驱动的结直肠癌化学预防中具有疗效。然而，糖尿病促进的结直肠癌带来了超越散发性结直肠癌的治疗挑战。本报告分析了由编码（n-6）至（n-3）PUFA去饱和酶的fat-1转基因产生的（n-3）PUFA以及合成的（n-3）PUFA模拟物（MEDICA类似物）在致癌物诱导的糖尿病促进动物模型中抑制结直肠癌发展的疗效。本文显示，致癌物诱导的结直肠癌在糖尿病背景下会因异常隐窝病灶（ACF）负荷增加、细胞增殖和上皮去分化而得到促进，同时伴有肝细胞核因子4α（HNF4α）、β-连环蛋白和β-连环蛋白反应基因表达增加。在糖尿病背景下引入fat-1转基因或口服MEDICA治疗，可改善糖尿病表型并消除结直肠癌，同时ACF负荷、细胞增殖以及HNF-4α、β-连环蛋白和β-连环蛋白反应基因的表达均降低。与（n-6）PUFA促进结直肠癌相反，（n-3）PUFA在消除结直肠癌发展方面的特异性在结直肠癌细胞系中也得到了类似验证。这些发现可能表明（n-3）PUFA或MEDICA在结直肠癌管理，特别是糖尿病促进的结直肠癌管理方面具有潜在的治疗前景。
