Role of NCOA5 in hepatic steatosis and hepatocarcinogenesis

描述（由申请人提供）：肝细胞癌（HCC）是全球第五大最常见和第三大最致命的癌症，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HCC患者在没有肝炎病毒感染和酗酒等显著病因的情况下发生HCC。新出现的证据表明，代谢性疾病，如非酒精性脂肪性肝病（NAFLD）和2型糖尿病（T2D），与HCC的发展有关，这可能是发达国家HCC发病率上升的原因。然而，这些疾病与HCC之间的联系机制在很大程度上仍然未知。我们的实验室最近证明，核受体共激活因子-5 （Ncoa5）表达减少与40%的人类HCC标本有关，并且在杂合敲除的雄性小鼠中，Ncoa5的单倍不足导致葡萄糖耐受不良、NAFLD和随后的HCC。这表明NCOA5缺陷驱动的致病途径在NAFLD、T2D和HCC中普遍存在。因此，我们假设NCOA5通过控制肝脏中编码关键促炎细胞因子和脂肪生成酶的基因的时间表达，作为单倍不足的肿瘤抑制因子。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HCC的发展。我们的目标是提供证据，证明NCOA5是控制肝脏炎症和脂质代谢的关键调节因子，其功能损害导致HCC的发展。这一假设将通过三个具体目标来验证：1)。利用细胞特异性Ncoa5敲除小鼠阐明肝脏炎症与HCC之间的分子联系；2)确定NCOA5缺陷驱动的NAFLD与HCC之间的分子联系；3)确定NCOA5异常表达在人hcc中的作用，建立NCOA5缺陷驱动小鼠与人hcc的分子关系。该方法具有创新性，因为它将遗传学控制代谢表型和系统级生物信息学方法与新型HCC小鼠模型相结合，以了解潜在的致癌途径和肝癌发生中隐藏的关键因素。本研究的重要意义在于，这些研究不仅为代谢性疾病与HCC之间的相互关系提供了独特的见解，而且为HCC预防和治疗方法的发展提供了新的靶点。

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.