Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Cancer Prev Res (Phila). 2011 Mar;4(3):396-403. doi: 10.1158/1940-6207.CAPR-10-0331.
Obesity and related metabolic abnormalities, including insulin resistance and a state of chronic inflammation, increase the risk of hepatocellular carcinoma. Abnormal activation of the insulin-like growth factor (IGF)/ IGF-1 receptor (IGF-1R) axis is also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of (-)-epigallocatechin gallate (EGCG), a major biologically active component of green tea, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks and then they received drinking water containing 0.1% EGCG for 34 weeks. At sacrifice, drinking water with EGCG significantly inhibited the development of liver cell adenomas in comparison with the control EGCG-untreated group. EGCG inhibited the phosphorylation of the IGF-1R, ERK (extracellular signal-regulated kinase), Akt, GSK-3β (glycogen synthase kinase-3β), Stat3, and JNK (c-Jun NH(2)-terminal kinase) proteins in the livers of experimental mice. The serum levels of insulin, IGF-1, IGF-2, free fatty acid, and TNF-α were all decreased by drinking EGCG, which also decreased the expression of TNF-α, interleukin (IL)-6, IL-1β, and IL-18 mRNAs in the livers. In addition, EGCG improved liver steatosis and activated the AMP-activated kinase protein in the liver. These findings suggest that EGCG prevents obesity-related liver tumorigenesis by inhibiting the IGF/IGF-1R axis, improving hyperinsulinemia, and attenuating chronic inflammation. EGCG, therefore, may be useful in the chemoprevention of liver tumorigenesis in obese individuals. Cancer Prev Res; 4(3); 396-403. ©2011 AACR.
肥胖症和相关代谢异常，包括胰岛素抵抗和慢性炎症状态，会增加肝细胞癌的风险。胰岛素样生长因子 (IGF)/IGF-1 受体 (IGF-1R) 轴的异常激活也与肥胖相关的肝肿瘤发生有关。在本研究中，我们研究了 (-)-表没食子儿茶素没食子酸酯 (EGCG)，绿茶的主要生物活性成分，对 C57BL/KsJ-db/db (db/db) 肥胖小鼠二乙基亚硝胺 (DEN) 诱导肝肿瘤发生发展的影响。雄性 db/db 小鼠给予含 40ppm DEN 的自来水 2 周，然后给予含 0.1% EGCG 的饮用水 34 周。处死时，与对照 EGCG 未处理组相比，EGCG 饮用水显著抑制了肝细胞腺瘤的发展。EGCG 抑制了 IGF-1R、ERK (细胞外信号调节激酶)、Akt、GSK-3β (糖原合成酶激酶-3β)、Stat3 和 JNK (c-Jun NH2-末端激酶) 蛋白在实验小鼠肝脏中的磷酸化。EGCG 还降低了血清胰岛素、IGF-1、IGF-2、游离脂肪酸和 TNF-α 水平，降低了 TNF-α、白细胞介素 (IL)-6、IL-1β 和 IL-18 mRNA 在肝脏中的表达。此外，EGCG 改善了肝脏脂肪变性并激活了肝脏中的 AMP 激活的蛋白激酶。这些发现表明，EGCG 通过抑制 IGF/IGF-1R 轴、改善高胰岛素血症和减轻慢性炎症来预防肥胖相关的肝肿瘤发生。因此，EGCG 可能有助于预防肥胖个体的肝肿瘤发生。Cancer Prev Res; 4(3); 396-403. ©2011 AACR.
