Bile Acid-Mediated IQGAP1 Regulation Drives Hepatic Tumorigenesis

项目总结/摘要 肝细胞癌（HCC）是世界范围内第二大致死性癌症，其发病率迅速上升。 在美国增加。这些发现强调了确定新的治疗方法的巨大需求， 以及HCC的早期诊断靶点。我们的实验室之前发现胆汁酸是一个家族， 内源性胆固醇代谢产物在肝脏中合成，能够激活促增殖雅普 （Yes相关蛋白）信号传导。重要的是，还发现这种雅普激活依赖于 支架蛋白IQ基序包含GT3活化蛋白1（IQGAP 1）。事实上， IQGAP 1与包括HCC在内的许多癌症的不良预后相关。符合本 假设，IQGAP 1已知调节和整合许多信号通路，这些信号通路通常 在癌症中上调的包括ERK、雅普、mTOR和EGFR。然而，IQGAP 1的监管仍然存在， 大部分未知。该提案旨在确定HCC开发期间IQGAP 1的调节和作用 通过确定（i）胆汁酸如何诱导IQGAP 1表达？和（ii）IQGAP 1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，其中法尼醇X受体（FXR）是进行下游转录的主要受体。 胆汁酸的影响我们的初步数据表明，在体外培养的小鼠中，增加的BA诱导了Iqgap 1 mRNA的表达。 剂量依赖性有趣的是，这种Iqgap 1 mRNA诱导在FXR特异性表达时被模拟。 GW 4064处理激活，表明胆汁酸可能通过FXR激活Iqgap 1表达。第一 本提案的目的是阐明负责IQGAP 1的BA受体和信号通路。的 第二个目标是重点描述IQGAP 1在肝脏肿瘤发展中的作用，并确定是否 IQGAP 1是胆汁酸促进肝肿瘤生长所必需的。二乙基亚硝胺（DEN） 将使用化学诱导的肝肿瘤发生的小鼠模型来实现该目的。成功 这项工作的完成将确定胆汁酸调节Iqgap 1的机制，并确定是否 操纵IQGAP 1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.