Dysadherin Promotes Cancer Stemness and Aggressiveness via FAK/YAP Axis in Hepatocellular Carcinoma

Abstract

Purpose: A significant barrier to effective cancer therapy is the ability of cancer stem-like cells (CSCs). Dysadherin is a cell membrane protein that contributes to cancer progression by conferring stem properties to hepatocellular carcinoma (HCC). In this study, we aim to investigate how dysadherin increases the HCC stemness and determine its underlying mechanism of action. Methods: The downstream mechanism of dysadherin in HCC stemness was screened by bioinfomatic analysis using a clinical genomic database of HCC. Next, we explored the physiological relevance and underlying mechanism of dysadherin on HCC aggressiveness using dysadherin knockout mouse model. Furthermore, the biological function of dysadherin in promoting CSC properties was confirmed by a gain and loss of function experiment. Results: The results of comprehensive bioinformatics analysis suggested that HCC patients expressing dysadherin at high levels were correlated with activation of the Yes-associated protein 1 (YAP) signaling pathway. Correspondingly, dysadherin deficiency reduced cancer stemness and aggressiveness in a mouse model of HCC by increasing YAP signaling. Furthermore, several functional studies have proven that dysadherin triggers the FAK/YAP/OCT4 axis in HCC to activate the CSC characteristics. Conclusions: Our findings elucidate the novel mechanism that dysadherin mediates the function of cancer stemness by FAK-YAP axis, which may represent a potential therapeutic strategy by suppressing cancer aggressiveness.