Bile Acid-Mediated IQGAP1 Regulation Drives Hepatic Tumorigenesis

项目摘要/摘要 摘要肝细胞癌是世界上第二大致死性癌症，其发病率迅速上升。 在美国越来越多。这些发现强调了确定新的治疗方法的巨大需要 以及肝细胞癌的早期诊断指标。我们实验室此前发现，胆汁酸是一类 在肝脏合成的内源性胆固醇代谢产物，能够激活促增殖的YAP (YES相关蛋白)信号。重要的是，还发现这种YAP激活依赖于一个 支架蛋白IQ基序含GTP酶激活蛋白1(IQGAP1)。事实上，过度表达 IQGAP1与包括肝细胞癌在内的许多癌症的预后不良有关。与此一致 假设，IQGAP1已知调节和整合了许多信号通路，这些信号通路通常是 在癌症中上调的基因包括ERK、YAP、mTOR和EGFR。然而，IQGAP1的监管仍然 很大程度上是未知的。本提案旨在确定IQGAP1在肝细胞癌发生发展中的调控和作用 通过确定(I)胆汁酸如何诱导IQGAP1的表达？和(Ii)IQGAP1在以下方面的贡献 促进肝脏肿瘤的发展？胆汁酸信号主要通过核受体增加 目的基因的转录，法尼醇X受体(FXR)是下游的主要转录因子 胆汁酸的影响。我们的初步数据证实，增加的bas在体外诱导了Iqgap1mRNA在 呈剂量依赖方式。有趣的是，当FXR特定时，这种Iqgap1 mRNA的诱导被模仿 被GW4064激活，提示胆汁酸可能通过FXR激活Iqgap1的表达。第一 本研究的目的是阐明BA受体(S)和信号通路(S)对IQGAP1的调控作用。这个 第二个目标是描述IQGAP1在肝肿瘤发生中的作用，并确定 IQGAP1是胆汁酸促进肝肿瘤生长所必需的。健壮的二乙基亚硝胺(DEN) 将使用化学诱导的肝肿瘤形成的小鼠模型来解决这一目标。成功 这项工作的完成将确定胆汁酸调节IqGap1的机制，并确定 调控IQGAP1的表达可能是限制肝肿瘤生长的有效策略。

Project Summary/Abstract Hepatocellular carcinoma (HCC) is the second most lethal cancer worldwide, and its incidence is rapidly increasing in the United States. These findings underscore the immense need to identify new therapeutic as well as early diagnostic targets for HCC. Our laboratory previously discovered that bile acids, a family of endogenous cholesterol metabolites synthesized in the liver, were able to activate the pro-proliferative YAP (Yes-Associated Protein) signaling. Importantly, it was also found that this YAP activation is dependent on a scaffolding protein IQ motif-containing GTPase Activating Protein 1 (IQGAP1). In fact, overexpression of IQGAP1 is associated with a poor prognosis in a number of cancers including HCC. Consistent with this hypothesis, IQGAP1 is known to regulate and integrate numerous signaling pathways, which are commonly upregulated in cancer including ERK, YAP, mTOR, and EGFR. However, the regulation of IQGAP1 remains largely unknown. This proposal aims to identify the regulation and role for IQGAP1 during HCC development by determining (i) How do bile acids induce IQGAP1 expression? and (ii) What is the contribution of IQGAP1 in promoting liver tumor development? Bile acids signal primarily through nuclear receptors to increase transcription of target genes with farnesoid X receptor (FXR) being the major one to carry out the downstream effects of bile acids. Our preliminary data identified that increased BAs induced Iqgap1 mRNA in vitro in a dose-dependent manner. Interestingly, this Iqgap1 mRNA induction was mimicked when FXR was specifically activated by GW4064 treatment, suggesting that bile acids may activate Iqgap1 expression via FXR. The first aim of this proposal is to elucidate the BA receptor(s) and signaling pathway(s) responsible for IQGAP1. The second aim is focused on delineating the role for IQGAP1 in liver tumor development and determining if IQGAP1 is necessary to drive hepatic tumor promotion by bile acids. The robust diethylnitrosamine (DEN) mouse model of chemically induced liver tumorigenesis will be used to address this aim. Successful completion of this work will identify the mechanism for Iqgap1 regulation by bile acids and determine if manipulating IQGAP1 expression can be an effective strategy to limit the growth of liver tumors.