Role of NCOA5 in hepatic steatosis and hepatocarcinogenesis

描述(申请人提供)：肝细胞癌是全球第五大常见癌症和第三大致命性癌症，在包括美国在内的发达国家发病率不断上升。据估计，15%-50%的肝癌患者在没有明显病因的情况下发展为肝癌，如肝炎、病毒感染和酗酒。新的证据表明，代谢紊乱，如非酒精性脂肪性肝病(NAFLD)和2型糖尿病(T2D)，与肝细胞癌的发生有关，这可能是发达国家肝细胞癌发病率上升的原因。然而，这些疾病和肝细胞癌之间联系的潜在机制在很大程度上仍然不清楚。我们的实验室最近证明，核受体辅活化子-5(NCOA5)的表达减少与40%的人类肝细胞癌标本有关，杂合子基因敲除雄性小鼠的NCOA5单倍体不足会导致葡萄糖耐量异常、NAFLD和随后的肝细胞癌。提示NAFLD、T2D和肝细胞癌共同存在NCOA5缺乏的致病途径。因此，我们假设NCOA5通过控制肝脏中编码关键致炎细胞因子和造脂酶的基因的时间表达而发挥单倍体不足的肿瘤抑制作用。因此，NCOA5功能障碍诱导促进肝脏炎症和脂肪生成的基因表达程序，导致肝细胞癌的发生。我们的目的是提供证据，证明NCOA5是控制肝脏炎症和脂质代谢的关键调节因子，其功能受损导致肝细胞癌的发生。这一假设将通过三个具体目标进行检验：1)。通过细胞特异性NCOA5基因敲除小鼠来阐明肝脏炎症和肝细胞癌之间的分子联系；2)确定NCOA5缺乏驱动的NAFLD和肝细胞癌之间的分子联系；以及3)确定NCOA5在人肝细胞癌中异常表达的作用，并在NCOA5缺乏驱动的小鼠和人肝细胞癌之间建立分子关系。这种方法是创新的，因为它结合了利用遗传学来控制代谢表型和系统水平的生物信息学方法，以及新的肝癌小鼠模型，以了解潜在的致癌途径和隐藏的肝癌发生的关键因素。这项拟议的研究具有重要意义，因为这些研究不仅将为代谢性疾病和肝癌之间的相互关系提供独特的见解，而且还将为开发预防和治疗肝癌的方法提供新的靶点。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the fifth most common and the third most lethal cancer worldwide, with increasing incidence in developed countries including the United States. It is estimated that 15-50% of HCC patients develop HCC in the absence of eminent etiological factors such as hepatitis viral infection and alcohol abuse. Emerging evidence has indicated that metabolic disorders, such as nonalcoholic fatty liver disease (NAFLD) and type-2 diabetes (T2D), are linked to HCC development, which may account for the increasing incidence of HCC in developed countries. However, mechanisms underlying the connection between these disorders and HCC remain largely unknown. Our laboratory has recently demonstrated that reduced nuclear receptor coactivator-5 (Ncoa5) expression is associated with 40% of human HCC specimens, and that haploinsufficiency of NCOA5 in heterozygous knockout male mice results in glucose intolerance, NAFLD and subsequent HCC. These suggest that a NCOA5 deficiency-driven pathogenic pathway is commonly shared by NAFLD, T2D and HCC. Therefore, we hypothesize that NCOA5 acts as a haploinsufficient tumor suppressor by controlling temporal expression of genes encoding key proinflammatory cytokines and lipogenic enzymes in the liver. Thus, dysfunction of NCOA5 induces gene expression programs promoting hepatic inflammation and lipogenesis, leading to HCC development. Our objective is to provide evidence that NCOA5 is a key regulator controlling hepatic inflammation and lipid metabolism and impairment of its function results in HCC development. This hypothesis will be tested by three specific aims: 1). Illustrate the molecular links between hepatic inflammation and HCC using cell specific Ncoa5 knockout mice; 2) Determine the molecular connections between NCOA5 deficiency-driven NAFLD and HCC; and 3) Determine the role of aberrant NCOA5 expression in human HCCs and establish a molecular relationship between NCOA5 deficiency-driven mouse and human HCCs. The approach is innovative, because it combines the use of genetics to control metabolic phenotypes and system-level bioinformatic methods with novel mouse models of HCC to understand the underlying oncogenic pathway and hidden key factors in hepatocarcinogenesis. The proposed research is significant because these studies will not only provide unique insight into the reciprocal relationship between metabolic diseases and HCC, but also new targets for the development of preventive and therapeutic approaches against HCC.