Bile Acid-Mediated IQGAP1 Regulation Drives Hepatic Tumorigenesis

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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.