(-)-Epigallocatechin Gallate Suppresses Azoxymethane-Induced Colonic Premalignant Lesions in Male C57BL/KsJ-db/db Mice
(-)-Epigallocatechin Gallate Suppresses Azoxymethane-Induced Colonic Premalignant Lesions in Male C57BL/KsJ-db/db Mice
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DOI：
10.1158/1940-6207.capr-08-0045
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发表时间：
2008-09-01
影响因子：
3.3
通讯作者：
Moriwaki, Hisataka
中科院分区：
文献类型：
--
作者：
Shimizu, Masahito;Shirakami, Yohei;Moriwaki, Hisataka
肥胖和糖尿病是结肠癌的危险因素。胰岛素样生长因子 (IGF)/IGF-IR 轴的激活在此致癌过程中发挥着关键作用。 (-)-表没食子儿茶素没食子酸酯 (EGCG) 是绿茶的主要成分，似乎具有抗肥胖和抗糖尿病作用。本研究探讨了 EGCG 对氧化偶氮甲烷诱导的 C57BL/KsJ-db/db (db/db) 小鼠结肠癌前病变发展的影响，这些小鼠肥胖并患有糖尿病。雄性 db/db 小鼠每周皮下注射四次。注射氧化偶氮甲烷（15毫克/公斤体重），然后饮用含有0.01％或0.1％EGCG的饮用水7周。处死时，饮用含有 EGCG 的水导致这些小鼠的异常隐窝灶总数、大异常隐窝灶和 β-连环蛋白累积隐窝的数量显着减少，所有这些都是结肠癌前病变。 db/db小鼠的结肠粘膜表达高水平的IGF-IR、磷酸化形式的IGF-IR (p-IGF-IR)、p-GSK-3β、β-连环蛋白、环氧合酶-2和细胞周期蛋白D1蛋白，并且饮用水中的EGCG导致这些蛋白的表达显着下降。用 EGCG 治疗这些小鼠还导致 IGFBP-3 的血清水平增加，同时 IGF-I、胰岛素、甘油三酯、胆固醇和瘦素的血清水平相反降低。 EGCG 克服了 IGF/IGF-IR 轴的激活，从而抑制肥胖相关结肠癌模型中结肠癌前病变的发展，该模型也与高脂血症、高胰岛素血症和高瘦素血症相关。因此，EGCG 可用于化学预防或治疗肥胖相关的结直肠癌。
Obesity and diabetes mellitus are risk factors for colon cancer. The activation of the insulin-like growth factor (IGF)/IGF-IR axis plays a critical role in this carcinogenesis. (-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, seems to have both antiobesity and antidiabetic effects. This study examined the effects of EGCG on the development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes mellitus. Male db/db mice were given four weekly s.c. injections of azoxymethane (15 mg/kg body weight) and then they received drinking water containing 0.01% or 0.1% EGCG for 7 weeks. At sacrifice, drinking water with EGCG caused a significant decrease in the number of total aberrant crypt foci, large aberrant crypt foci, and beta-catenin accumulated crypts in these mice, all of which are premalignant lesions of the colon. The colonic mucosa of db/db mice expressed high levels of the IGF-IR, phosphorylated form of IGF-IR (p-IGF-IR), p-GSK-3 beta, beta-catenin, cyclooxygenase-2, and cyclin D1 proteins, and EGCG in drinking water caused a marked decrease in the expression of these proteins. Treating these mice with EGCG also caused an increase in the serum level of IGFBP-3 while conversely decreasing the serum levels of IGF-I, insulin, triglyceride, cholesterol, and leptin. EGCG overcomes the activation of the IGF/IGF-IR axis, thereby inhibiting the development of colonic premalignant lesions in an obesity-related colon cancer model, which was also associated with hyperlipidemia, hyperinsulinemia, and hyperleptinemia. EGCG may be, therefore, useful in the chemoprevention or treatment of obesity-related colorectal cancer.