Ohno Tomohiko, Shimizu Masahito, Shirakami Yohei, Baba Atsushi, Kochi Takahiro, Kubota Masaya, Tsurumi Hisashi, Tanaka Takuji, Moriwaki Hisataka
Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
PLoS One. 2015 Apr 16;10(4):e0124081. doi: 10.1371/journal.pone.0124081. eCollection 2015.
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.
肥胖及相关代谢紊乱，如糖尿病，会增加肝癌发生的风险。广泛用于治疗糖尿病的二甲双胍可改善胰岛素敏感性。二甲双胍还被认为具有抗肿瘤活性并能降低癌症风险。本研究检测了二甲双胍对二乙基亚硝胺（DEN）诱导的C57BL/KsJ-+Leprdb/+Leprdb（db/db）肥胖糖尿病小鼠肝脏肿瘤发生的预防作用。小鼠在2周龄时单次注射DEN，随后饮用含二甲双胍的水20周。给予二甲双胍显著降低了肝脏癌前病变的数量并抑制了肝细胞肿瘤。二甲双胍还显著降低了血清胰岛素水平并减轻了胰岛素抵抗，且抑制了肝脏中Akt、雷帕霉素哺乳动物靶蛋白（mTOR）和p70S6的磷酸化。此外，二甲双胍降低了血清瘦素水平，同时提高了脂联素水平。这些发现表明，二甲双胍通过改善胰岛素敏感性、抑制Akt/mTOR/p70S6信号通路的激活以及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化学预防的有力候选药物。
