A molecular mechanism whereby metformin protects against liver cancer

描述(由申请人提供)：非酒精性脂肪性肝病(NAFLD)和2型糖尿病(T2D)与肝细胞癌(HCC)风险增加有关，而接受二甲双胍治疗的T2D患者降低了肝细胞癌的发病率和死亡率。虽然已经报道了几种因素可能介导了二甲双胍对几种类型癌症风险的预防作用，但二甲双胍降低肝癌风险的确切机制在很大程度上仍不清楚。具体地说，目前尚不清楚二甲双胍靶向的哪些细胞因子在糖尿病患者发生肝癌的过程中起关键作用，以及哪些患者亚群可能对二甲双胍治疗更敏感。我们的长期目标是了解肝细胞癌的分子基础。这项建议的目的是揭示二甲双胍抑制携带核受体辅活化子-5(NCOA5)基因杂合缺失的小鼠自发肝癌发展的机制，并改进现有工具，利用已识别的基因和信号来预测肝癌患者的预后和对二甲双胍的反应。中心假设是，在糖尿病的情况下，NCOA5表达减少是肝癌发生的关键风险因素，二甲双胍通过减少肝脏胰岛素抵抗和脂肪变性来保护小鼠免受肝癌发展，部分是通过积极调节NCOA5的表达。这项拟议研究的基本原理是，旨在增加NCOA5表达或针对NCOA5缺乏驱动的致癌途径的治疗策略，在预防肝癌方面具有潜在的有效作用。这一假设将通过两个特定的目标进行检验：1)利用一种新的肝癌基因工程小鼠模型(NCOA5+/-小鼠)，确定二甲双胍对肝癌发展和NCOA5在肝脏中表达的影响；2)在二甲双胍介导的肝癌保护中，识别和翻译关键靶点和途径，从小鼠肝癌模型到人肝癌模型。这种方法是创新的，因为它利用了一种新的肝癌基因工程NCOA5+/-小鼠模型来分析二甲双胍在肝癌发生中的作用，并确定了预测肝癌患者预后的新基因和基因标志。这项拟议的研究具有重要意义，因为它有望建立一个新的概念，即二甲双胍抑制NCOA5缺乏诱导的致病途径，这是NAFLD、T2D和肝癌共同的。这不仅有助于我们对肝细胞癌发病机制的认识，而且为预测肝细胞癌患者的复发风险和二甲双胍相关治疗的疗效提供了更好的生物标志物。

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) and type-2 diabetes (T2D) are associated with increased risk of hepatocellular carcinoma (HCC), and individuals with T2D treated with metformin have a reduced risk of HCC incidence and mortality. Although several factors have been reported to probably mediate the preventive effect of metformin on the risk of several types of cancers, a precise mechanism by which metformin reduces HCC risk remains largely unknown. Specifically, it is not known what cellular factors, targeted by metformin, are critical in the development of HCC in diabetic patients, and which sub- population of patients may be more responsive to metformin treatment. Our long-term goal is to understand the molecular basis of HCC. The objective of this proposal is to unveil the mechanism by which metformin inhibits spontaneous HCC development in mice bearing a heterozygous deletion of the nuclear receptor coactivator-5 (Ncoa5) gene and improve current tools utilizing identified genes and signatures to predict prognosis and response to metformin in patients with HCC. The central hypothesis is that reduced Ncoa5 expression is a key risk factor for HCC development in the context of a diabetic condition, and metformin protects mice against HCC development by reducing hepatic insulin resistance and steatosis, in part by positively regulating the expression of Ncoa5. The rationale for the proposed research is that therapeutic strategies, aimed at increasing Ncoa5 expression or targeting Ncoa5 deficiency driven oncogenic pathways, are potentially effective in protecting against HCC. This hypothesis will be tested by two specific aims: 1) determine the effect of metformin on HCC development and Ncoa5 expression in the liver using a novel genetically-engineered mouse model (Ncoa5+/- mice) of HCC, and 2) identify and translate critical targets and pathways, in metformin-mediated protection against HCC, from a mouse model of HCC to human HCC. The approach is innovative because it utilizes a novel genetically-engineered Ncoa5+/- mouse model of HCC to analyze the effects of metformin on hepatocarcinogenesis and identifies new genes and gene signatures for predicting the prognosis of patients with HCC. The proposed research is significant because it is expected to establish a new concept that metformin inhibits an Ncoa5 deficiency-induced pathogenic pathway that is commonly shared by NAFLD, T2D and HCC. This will not only advance our understanding of the etiological mechanisms of HCC, but also provide better biomarkers for predicting the risk of recurrence and response to metformin related therapy in patients with HCC.