12514 Elucidating The Interactions Between IQGAP1-YAP-ECM Stiffness In Liver Cancer

Abstract Disclosure: S.E. Hobbs: None. H. Kimmel: None. G. Underhill: None. S. Anakk: None. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer associated-deaths worldwide. Complex signaling mechanisms and several cellular processes in cancer are coordinated using scaffolding proteins. One such scaffold, IQ motif-containing GTPase Activating Protein 1 (IQGAP1) is associated with metastasis, inflammation and tumor growth. Previous work has shown that overexpression of IQGAP1 activates Yes-associated Protein (YAP) in mice and both proteins are induced in clinical HCC samples. Conversely, we found YAP inhibition, also reduces IQGAP1 levels. Extracellular matrix (ECM) stiffness, due to liver fibrosis in HCC, can activate YAP to promote tumor progression. Our preliminary data show that IQGAP1 protein stains in a punctate manner. The characteristics of this puncta are being investigated currently. Remarkably, we find IQGAP1 protein induction and predominant localization at the plasma membrane when HepG2 cells (an HCC cell line) are grown onto a stiff ECM (25 kPa). But the stiffness did not change the IQGAP1 transcript levels. ECM stiffness led to IQGAP1 induction, and high YAP staining in the nucleus. Intriguingly, we find that IQGAP1 colocalizes with actin, a mediator of biomechanical signals in HepG2 cells. This colocalization with actin is maintained irrespective of the stiffness. When we inhibit the actin polymerization with LatA, we noted increased IQGAP1 protein expression. Based on this data, we speculate that IQGAP1 levels may be regulated by actin dynamics and that IQGAP1-Actin-YAP-Stiffness impact hepatic carcinogenesis. Presentation: 6/2/2024