THU497 Elucidating The Role Of The IQGAP1-YAP Axis In ECM Stiffness-Mediated Hepatocellular Carcinoma Progression

Abstract

Abstract Disclosure: S.E. Hobbs: None. H. Kimmel: None. G. Underhill: None. S. Anakk: None. Hepatocellular Carcinoma (HCC), the primary form of liver cancer, is the second leading cause of cancer associated-associated deaths worldwide. Complex signaling mechanisms and several cellular processes are coordinated using scaffolding proteins. IQ motif-containing GTPase Activating Protein 1 (IQGAP1) is a scaffolding protein that is overexpressed in multiple epithelial cancers, including ovarian, breast, and liver. Previous work has shown that overexpression of IQGAP1 activates Yes-associated Protein (YAP) to promote HCC in mice. Extracellular matrix (ECM) stiffness, due to liver fibrosis in HCC, can activate YAP to promote tumor progression. Remarkably, our preliminary data show that IQGAP1 has increased localization at the plasma membrane when HepG2 cells (an HCC cell line) are seeded onto a stiff ECM (25 kPa). YAP is modulated by actin dynamics, which can be altered by changes in the plasma membrane. Therefore, IQGAP1’s movement to the plasma membrane can potentially activate YAP by modulating actin dynamics. We also found that the anti-HCC drug sorafenib, can induce the expression IQGAP1 and activate YAP in HepG2 cells grown on plastic. These sorafenib-mediated changes are counterproductive and can contribute to drug resistance of HCC. Finally, we found that inhibition of YAP in HepG2 cells significantly decreases IQGAP1 expression, indicating that there is bidirectional crosstalk between the two proteins. Future directions will elucidate if loss of IQGAP1 decreases ECM stiffness-induced YAP activation, proliferation, and migration in HCC cells. In addition, we will determine if ECM stiffness alters sorafenib-mediated IQGAP1 upregulation, as ECM stiffness has been linked to drug resistance in HCC. Overall, this work will shed light on the potential role of the IQGAP1-YAP axis in ECM stiffness-mediated HCC progression. Presentation: Thursday, June 15, 2023