Supervillin promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma in hypoxia via activation of the RhoA/ROCK-ERK/p38 pathway

Abstract

Tumor recurrence in HCCs is, in part, attributed to increased EMT, as well as enhanced tumor cell aggression and treatment resistance [15, 16]. [...]investigation of the mechanisms driving tumor EMT and cell migration/invasion is essential for the development of treatments for malignancies in HCC patients. Supervillin is also a component of invadosomes, where it regulates the invadosome half-life and matrix degradation, and enhances the secretion of matrix metalloproteinases (MMPs) [29–31]. [...]supervillin promotes cancer cell survival through integrin-based adhesions via its crosstalk between ERK-mediated survival signaling and cell motility pathways that contribute to ERK signaling [34, 35, 40]. The results of the current study demonstrated that hypoxia elicits an upregulation in the expression of supervillin, which was a significant and independent predictor of cancer metastasis and poor survival in HCC patients. [...]the RhoA/ROCK-ERK/p38 signaling pathway and RhoA-mediated actin polymerization are systematically connected, contributing to HCC cell metastasis mediated by supervillin (Fig. 7g). Since this organization of actin structures is mediated by Rho proteins such as Cdc42, Rac1, and RhoA, we decided to investigate the relationship between Rho GTPases and supervillin function in HCC cell lines under hypoxic conditions.