A molecular mechanism whereby metformin protects against liver cancer

描述（由申请方提供）：非酒精性脂肪肝（NAFLD）和2型糖尿病（T2 D）与肝细胞癌（HCC）风险增加相关，接受二甲双胍治疗的T2 D患者HCC发病率和死亡率风险降低。尽管有几种因素可能介导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HCC风险的确切机制在很大程度上仍然未知。具体而言，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HCC中至关重要，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HCC的分子基础。该提案的目的是揭示二甲双胍抑制核受体辅激活因子-5（Ncoa 5）基因杂合缺失小鼠自发性HCC发展的机制，并利用已鉴定的基因和特征来改善当前的工具，以预测HCC患者对二甲双胍的预后和反应。中心假设是Ncoa 5表达降低是糖尿病条件下HCC发展的关键风险因素，二甲双胍通过减少肝脏胰岛素抵抗和脂肪变性（部分通过正调节Ncoa 5的表达）保护小鼠免受HCC发展。这项研究的基本原理是，旨在增加Ncoa 5表达或靶向Ncoa 5缺陷驱动的致癌途径的治疗策略可能有效地预防HCC。该假设将通过两个特定目的进行检验：1）使用HCC的新型基因工程小鼠模型（Ncoa 5 +/-小鼠）确定二甲双胍对HCC发展和肝脏中Ncoa 5表达的影响，以及2）鉴定并翻译二甲双胍介导的HCC保护中的关键靶标和途径，从HCC的小鼠模型到人HCC。该方法具有创新性，因为它利用了一种新的基因工程Ncoa 5 +/-小鼠HCC模型来分析二甲双胍对肝癌发生的影响，并确定了用于预测HCC患者预后的新基因和基因特征。这项拟议的研究意义重大，因为它有望建立一个新的概念，即二甲双胍抑制NAFLD，T2 D和HCC共同的Ncoa 5缺陷诱导的致病途径。这不仅将促进我们对HCC病因机制的理解，还将为预测HCC患者的复发风险和二甲双胍相关治疗的反应提供更好的生物标志物。

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.