Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-+Leprdb/+Leprdb mice.
Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-+Leprdb/+Leprdb mice.
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DOI：
10.1371/journal.pone.0124081
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Moriwaki H
中科院分区：
文献类型：
--
作者：
Ohno T;Shimizu M;Shirakami Y;Baba A;Kochi T;Kubota M;Tsurumi H;Tanaka T;Moriwaki H
肥胖和相关的代谢紊乱，如糖尿病，增加了肝癌发生的风险。广泛用于治疗糖尿病的二甲双胍可改善胰岛素敏感性。二甲双胍也被认为具有抗肿瘤活性并降低癌症风险。本研究检查了二甲双胍对C57 BL/KsJ-+Leprdb/+Leprdb（db/db）肥胖和糖尿病小鼠中二乙基亚硝胺（DEN）诱导的肝脏肿瘤发生的预防作用。在2周龄时给予小鼠单次注射DEN，随后给予含有二甲双胍的饮用水20周。二甲双胍给药显著降低了肝脏癌前病变的多样性，并抑制了肝细胞肿瘤。二甲双胍还显著降低血清胰岛素水平，降低胰岛素抵抗，并抑制Akt、哺乳动物雷帕霉素靶蛋白（mTOR）和肝脏中p70 S6的磷酸化。此外，二甲双胍可降低血清瘦素水平，而升高脂联素水平。这些结果表明，二甲双胍通过改善胰岛素敏感性、抑制Akt/mTOR/p70 S6信号转导激活和改善脂肪因子失衡来预防肝脏肿瘤发生。因此，二甲双胍可能是肥胖或糖尿病患者肝脏肿瘤发生化学预防的有效候选药物。
Obesity and related metabolic disorders, such as diabetes mellitus, raise the risk of liver carcinogenesis. Metformin, which is widely used in the treatment of diabetes, ameliorates insulin sensitivity. Metformin is also thought to have antineoplastic activities and to reduce cancer risk. The present study examined the preventive effect of metformin on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db) obese and diabetic mice. The mice were given a single injection of DEN at 2 weeks of age and subsequently received drinking water containing metformin for 20 weeks. Metformin administration significantly reduced the multiplicity of hepatic premalignant lesions and inhibited liver cell neoplasms. Metformin also markedly decreased serum levels of insulin and reduced insulin resistance, and inhibited phosphorylation of Akt, mammalian target of rapamycin (mTOR), and p70S6 in the liver. Furthermore, serum levels of leptin were decreased, while those of adiponectin were increased by metformin. These findings suggest that metformin prevents liver tumorigenesis by ameliorating insulin sensitivity, inhibiting the activation of Akt/mTOR/p70S6 signaling, and improving adipokine imbalance. Therefore, metformin may be a potent candidate for chemoprevention of liver tumorigenesis in patients with obesity or diabetes.
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影响因子：
24.5
作者：
Chen, Hsiao-Ping;Shieh, Jeng-Jer;Wu, Chun-Ying
通讯作者：
Wu, Chun-Ying
影响因子：
4.2
作者：
Cai, Xianbin;Hu, Xi;Jing, Xubin
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Jing, Xubin
影响因子：
13.5
作者：
Kitade, Mitsuteru;Yoshiji, Hitoshi;Fukui, Hiroshi
通讯作者：
Fukui, Hiroshi
影响因子：
5.8
作者：
Kang, S;Song, J;Park, D
通讯作者：
Park, D
影响因子：
158.5
作者：
Calle, EE;Rodriguez, C;Thun, MJ
通讯作者：
Thun, MJ