Integrin-YAP/TEAD Feedback Loop Promotes Tumor Invasion by Enhanced Cell Adhesion and Cell Proliferation in Hepatocellular Carcinoma

Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer with a high mortality rate. Hepatocellular carcinoma cells are known to invade surrounding tissues and organs which is a complicated process involving a number of unknown variables, such as many signaling pathways (e.g., integrins and IL-6/STAT3) or mechanical factors (e.g., stiffness). Finding successful therapies would benefit from knowing the specifics of the molecular mechanisms behind cellular activities (cell adhesion, migration, and proliferation). In this paper, we found that ITGB1, YAP1, TEAD1/3 expressions were all upregulated in tumor tissue, and ITGB1 had a significant positive correlation with YAP1 and TEAD1/3. We demonstrated through experiments and mathematical modeling that YAP/TEAD could regulate the expression of ITGB1, thus forming an obvious ITGB1-YAP/TEAD positive feedback loop. The experimental results also showed that PFL significantly enhanced the cell proliferation and migration ability. Finally, we used the cellular Potts model (CPM) to demonstrate that tumor cells with ITGB1-YAP/TEAD positive feedback loop can significantly have a stronger invasive capacity.