A molecular mechanism whereby metformin protects against liver cancer

二甲双胍预防肝癌的分子机制

• 批准号: 8686434
• 负责人: HUA XIAO
• 金额: $ 18.97万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686434
• 关键词: AF2; Activator Appliances; Basic Science; Biological Markers; Colon Carcinoma; Development; Diet; Epidemiologic Studies; Etiology; Exhibits; Fatty Liver; Fatty-acid synthase; Gene Expression; Gene Targeting; Genes; Genetic Engineering; Genetic screening method; Genetically Engineered Mouse; Glucose Intolerance; Goals; Growth; Hepatic; Hepatocarcinogenesis; Human; Incidence; Individual; Insulin Resistance; Knock-out; Link; Liver; Liver diseases; Liver neoplasms; London; Malignant Epithelial Cell; Malignant neoplasm of liver; Mediating; Metformin; Mission; Molecular; Mus; Neoplasm Metastasis; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Prevention; Preventive; Primary carcinoma of the liver cells; Public Health; Recurrence; Reporting; Research; Risk; Risk Factors; Role; Specimen; Testing; Therapeutic; Translating; Work; Xenograft procedure; base; cancer type; diabetic; diabetic patient; improved; innovation; insight; male; mortality; mouse model; non-alcoholic fatty liver; novel; outcome forecast; patient population; pre-clinical research; public health relevance; response; tool

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.

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）风险增加相关，T2D患者接受二甲双胍治疗可降低HCC发病率和死亡率。尽管有报道称有几个因素可能介导二甲双胍对几种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HCC的发展中起关键作用，以及哪些亚群患者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。本研究的目的是揭示二甲双胍抑制核受体共激活因子-5 （Ncoa5）基因杂合缺失小鼠自发性HCC发展的机制，并改进现有工具，利用已识别的基因和特征来预测HCC患者的预后和对二甲双胍的反应。核心假设是，在糖尿病情况下，Ncoa5表达减少是HCC发展的关键危险因素，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HCC的发展，部分是通过积极调节Ncoa5的表达。提出这项研究的基本原理是，旨在增加Ncoa5表达或靶向Ncoa5缺乏驱动的致癌途径的治疗策略可能有效地预防HCC。这一假设将通过两个特定目标进行验证：1)利用一种新型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肝脏中Ncoa5表达的影响；2)从小鼠肝癌模型到人类肝癌模型，确定并翻译二甲双胍介导的肝癌保护的关键靶点和途径。该方法具有创新性，因为它利用一种新的基因工程Ncoa5+/-小鼠肝癌模型来分析二甲双胍对肝癌发生的影响，并识别新的基因和基因特征，用于预测HCC患者的预后。这项研究具有重要意义，因为它有望建立一个新的概念，即二甲双胍抑制NAFLD、T2D和HCC共有的Ncoa5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，而且还将为预测HCC患者复发风险和对二甲双胍相关治疗的反应提供更好的生物标志物。