Bile Acid-Mediated IQGAP1 Regulation Drives Hepatic Tumorigenesis

胆汁酸介导的 IQGAP1 调节驱动肝脏肿瘤发生

• 批准号: 9914233
• 负责人: Hanna Erickson
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-16 至 2022-02-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914233
• 关键词: Address; Affect; Age-Months; Autopsy; Bile Acids; Binding Sites; Biological Assay; Cell Culture Techniques; Cell Line; Cell physiology; Cell-Cell Adhesion; Cells; Cessation of life; Chemical Models; Chenodeoxycholic Acid; Cholesterol; Cholic Acids; Cycloheximide; Dactinomycin; Data; Dependence; Development; Diagnostic; Diet; Diethylnitrosamine; Dose; Epidermal Growth Factor Receptor; FRAP1 gene; Family; Fatty acid glycerol esters; Female; Fibrosis; GPBAR1 gene; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Gold; Growth; HNF4A gene; HepG2; Hepatic; Hepatocarcinogenesis; Hepatocyte; Histologic; IQ motif containing GTPase activating protein 1; Immunofluorescence Immunologic; In Vitro; Incidence; Inflammation; Introns; Kupffer Cells; Laboratories; Lesion; Letters; Ligands; Link; Lithocholic Acid; Liver; Liver diseases; Liver neoplasms; Luciferases; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Messenger RNA; Modeling; Molecular; Monitor; Mus; Necrosis; Nuclear Receptors; Pathway interactions; Patients; Prevalence; Primary carcinoma of the liver cells; Prognostic Factor; Proteins; RNA; Receptor Signaling; Regulation; Role; Scaffolding Protein; Sex Differences; Signal Pathway; Signal Transduction; Site; Testing; Time; Translations; Tumor Promotion; United States; Work; absorption; angiogenesis; base; cancer cell; cancer diagnosis; cell motility; cell type; cohort; deletion analysis; delta opioid receptor; design; effective therapy; extracellular; in silico; in vivo; knock-down; liver cell proliferation; mRNA Expression; male; migration; mouse model; new therapeutic target; novel therapeutics; outcome forecast; overexpression; pregnane X receptor; promoter; protein activation; protein expression; pup; receptor; receptor binding; response; small hairpin RNA; stellate cell; therapeutic target; transcription factor; tumor; tumor progression; tumorigenesis

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.

项目概要/摘要 肝细胞癌（HCC）是全球第二大致命癌症，其发病率迅速上升 在美国不断增加。这些发现强调迫切需要确定新的治疗方法 以及 HCC 的早期诊断目标。我们的实验室之前发现胆汁酸是一个家族 在肝脏中合成的内源性胆固醇代谢物能够激活促增殖的 YAP （是相关蛋白）信号传导。重要的是，还发现此 YAP 激活依赖于 支架蛋白 IQ 基序包含 GTP 酶激活蛋白 1 (IQGAP1)。事实上，过度表达 IQGAP1 与包括 HCC 在内的多种癌症的不良预后相关。与此一致 假设，已知 IQGAP1 可以调节和整合许多信号通路，这些通路通常是 在癌症中上调，包括 ERK、YAP、mTOR 和 EGFR。然而，IQGAP1 的监管仍然存在 很大程度上不为人知。该提案旨在确定 IQGAP1 在 HCC 发展过程中的调控和作用 通过确定 (i) 胆汁酸如何诱导 IQGAP1 表达？ (ii) IQGAP1 在以下方面有何贡献？ 促进肝肿瘤的发展？胆汁酸主要通过核受体发出信号以增加 靶基因的转录，以法尼醇X受体（FXR）为主要进行下游 胆汁酸的影响。我们的初步数据表明，增加的 BA 在体外诱导 Iqgap1 mRNA 剂量依赖性方式。有趣的是，当 FXR 被特异性地刺激时，这种 Iqgap1 mRNA 诱导被模仿。 GW4064 处理激活，表明胆汁酸可能通过 FXR 激活 Iqgap1 表达。第一个 该提案的目的是阐明负责 IQGAP1 的 BA 受体和信号通路。这 第二个目标是描绘 IQGAP1 在肝肿瘤发展中的作用并确定是否 IQGAP1 对于胆汁酸促进肝肿瘤的发生是必需的。强大的二乙基亚硝胺 (DEN) 化学诱导肝脏肿瘤发生的小鼠模型将用于实现这一目标。成功的 这项工作的完成将确定胆汁酸调节 Iqgap1 的机制，并确定是否 控制 IQGAP1 表达可能是限制肝脏肿瘤生长的有效策略。