(PQ6)Nuclear receptor mechanisms in circadian disruption induced hepatocarcinogenesis

项目摘要 本申请通过研究NCI PQ 6关于昼夜节律过程如何影响肿瘤发展的问题， 非酒精性脂肪性肝病（NAFLD）中核受体通路的昼夜节律功能障碍的作用- 诱发肝细胞癌（HCC）。 肝癌，以前被认为是一种罕见的癌症在西方世界，已增加了3倍的发病率，因为 20世纪80年代，由于癌症死亡率的增加， 在发病机制上缺乏认识。HCC风险增加与 与肥胖相关的NAFLD的流行有关，NAFLD最近已成为HCC的主要危险因素。 然而，目前还没有有效的方法来预防、早期诊断和治疗NAFLD诱导的HCC。 目前可用。NAFLD相关HCC的风险增加与人群范围内的慢性 昼夜节律紊乱是人类肥胖、NAFLD和癌症的常见风险因素。我们最近 根据人类夜班时间表建立了时差小鼠模型。我们发现慢性时差反应 在野生型小鼠中诱导代谢综合征、NAFLD和HCC 与肥胖人群中观察到的惊人相似，NAFLD进展为非酒精性 脂肪性肝炎（NASH）和纤维化。我们将肝内胆汁淤积确定为 促进NAFLD诱导的HCC的关键病理生理机制，并证明昼夜节律 核受体FXR和CAR途径的失调是一种重要的致癌机制， 驱动胆汁淤积和毒性胆汁酸信号传导，以促进从NAFLD到NASH，纤维化， 最后是HCC。 在本申请中，我们提出3个目标。1)定义FXR和CAR控制的肝脏的昼夜节律特征 基因网络和时差引起的这些基因网络的失调签名。2)定义的作用 Ctnnb 1和Tp 53等癌基因突变在时差诱发肝癌前病变进展中的作用 HCC病变和基因特征的昼夜节律谱以及与HCC相关的血清生物标志物 肝癌发生3)测试FXR激动剂奥贝胆酸（OCA）和CAR的预测能力 反向激动剂雄甾烷醇（ANDR），以防止时差引起的胆汁淤积和HCC。 这些研究将显著提高我们对昼夜节律功能障碍在 一般自发性致癌作用，特别是NEDD诱导的肝癌作用。他们将 还阐明了新的和令人兴奋的途径，以开发新的时间治疗战略， 在人类中治疗NAFLD诱导的HCC。

Project Summary This application addresses NCI PQ6 on how circadian processes affect tumor development by studying the role of circadian dysfunction of nuclear receptor pathways in non-alcoholic fatty liver disease (NAFLD)- induced hepatocellular carcinoma (HCC). HCC, previously considered a rare cancer in the Western world, has increased 3-fold in incidence since the 1980s, and is currently the fastest rising cause of cancer-related death in the U.S, due to an increase in incidence in combination of lack of understanding of its mechanism. The increased HCC risk is coupled with the prevalence of obesity-related NAFLD, which has recently become the leading risk factor for HCC. However, no efficient approaches for prevention, early diagnosis, and treatment of NAFLD-induced HCCs are currently available. The increased risk of NAFLD-related HCC is coupled with population-wide chronic circadian disruption, a common risk factor of obesity, NAFLD, and cancer in humans. We have recently established a jet-lagged mouse model following a human nightshift schedule. We found that chronic jet-lag induces metabolic syndrome, NAFLD, and HCC in wild-type mice following a pathophysiological pathway strikingly similar to that observed in obese humans, with NAFLD progressing to nonalcoholic steatohepatitis (NASH) and fibrosis prior to HCC detection. We identified intrahepatic cholestasis as the key pathophysiological mechanism promoting NAFLD-induced HCC, and demonstrated that circadian dysregulation of nuclear receptor FXR and CAR pathways is an essential oncogenic mechanism that drives cholestasis and toxic bile acid signaling to promote the progression from NAFLD to NASH, fibrosis, and eventually HCC. In this application, we propose 3 aims. 1) Define the circadian profiles of FXR and CAR controlled hepatic gene networks and jet-lag induced deregulation signatures of these gene networks. 2) Define the role of Ctnnb1 and Tp53 and other oncogenic mutations in the progression from jet-lag induced liver premalignant lesions to HCC and the circadian profiles of gene signatures as well as serum biomarkers associated with hepatocarcinogenesis. 3) Test the predicted abilities of FXR agonist obeticholic acid (OCA) and CAR inverse agonist androstanol (ANDR) to prevent jet-lag induced cholestasis and HCC. These studies will significantly improve our understanding of the role of circadian dysfunction in spontaneous carcinogenesis in general, and NFALD-induced hepatocarcinogenesis in particular. They will also illuminate new and exciting avenues to develop novel chronotherapy strategies for prevention and treatment of NAFLD-induced HCC in humans.