Suppressive effects of nobiletin on hyperleptinemia and colitis-related colon carcinogenesis in male ICR mice
Suppressive effects of nobiletin on hyperleptinemia and colitis-related colon carcinogenesis in male ICR mice
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DOI：
10.1093/carcin/bgn080
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发表时间：
2008-05-01
期刊：
影响因子：
4.7
通讯作者：
Murakami, Akira
中科院分区：
文献类型：
--
作者：
Miyamoto, Shingo;Yasui, Yumiko;Murakami, Akira
脂肪细胞因子是一组脂肪细胞分泌的蛋白质，对脂质和碳水化合物的代谢以及许多其他过程有重要影响。最近的一些研究表明，一些脂肪细胞因子可能在体外显著影响恶性细胞的增殖，而它们在体内是否具有类似的作用尚不清楚。在这项研究中，我们测定了偶氮氧甲烷(AOM)-和葡聚糖硫酸钠（DSS）诱导结肠癌小鼠血清中脂肪细胞因子的水平。5周龄ICR小鼠单次腹腔注射AOM，然后在饮用水中添加1% DSS，连续7天。黄酮（NOB）是一种柑橘类黄酮，在日粮中给予（100p . p.m.） 17周。然后在第20周末测定结肠肿瘤的发生率和数量以及血清脂肪细胞因子的浓度。AOM/ dss处理小鼠血清瘦素水平比未处理小鼠高6倍，而甘油三酯、脂联素和白细胞介素-6水平无显著差异。饲喂NOB可消除结肠恶性肿瘤，血清瘦素水平显著降低75%。此外，在分化的3T3-L1小鼠脂肪细胞中，NOB通过使丝裂原活化的蛋白激酶/细胞外信号调节的蛋白激酶失活，抑制瘦素依赖但非独立的HT-29结肠癌细胞的增殖，减少瘦素分泌，但不影响脂联素的分泌，并呈剂量依赖性。综上所述，我们的研究结果表明，小鼠血清中较高水平的瘦素促进结肠癌的发生，而NOB对结肠癌的发生具有化学预防作用，部分是通过调节瘦素水平来实现的。
Adipocytokines are a group of adipocyte-secreted proteins that have significant effects on the metabolism of lipids and carbohydrates, as well as numerous other processes. A number of recent studies have indicated that some adipocytokines may significantly influence the proliferation of malignant cells in vitro, whereas it remains unclear whether they have similar roles in vivo. In this study, we determined serum levels of adipocytokines in mice with azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced colon carcinogenesis. Five-week-old ICR mice were given a single intraperitoneal injection of AOM followed by 1% DSS in drinking water for 7 days. Nobiletin (NOB), a citrus flavonoid, was given in the diet (100 p.p.m) for 17 weeks. Thereafter, the incidence and number of colon tumors and serum concentration of adipocytokines were determined at the end of week 20. The serum leptin level in AOM/DSS-treated mice was six times higher than that in untreated mice, whereas there were no significant differences in the levels of triglycerides, adiponectin and interleukin-6. Feeding with NOB abolished colonic malignancy and notably decreased the serum leptin level by 75%. Further, NOB suppressed the leptin-dependent, but not independent, proliferation of HT-29 colon cancer cells and decreased leptin secretion through inactivation of mitogen-activated protein kinase/extracellular signaling-regulated protein kinase, but not that of adiponectin in differentiated 3T3-L1 mouse adipocytes in a dose-dependent manner. Taken together, our results suggest that higher levels of leptin in serum promote colon carcinogenesis in mice, whereas NOB has chemopreventive effects against colon carcinogenesis, partly through regulation of leptin levels.