FAM21C Promotes Hepatocellular Carcinoma Invasion and Metastasis by Driving Actin Cytoskeleton Remodeling via Inhibiting Capping Ability of CAPZA1.

Yao Lu,Juxian Song,Shuguo Zheng,Jialong Liu,Deng Huang,Baolin Wang,Bowen Zheng

doi:10.3389/fonc.2021.809195

Abstract

Hepatocellular carcinoma (HCC) is characterized by a high incidence of metastasis. The dynamic remodeling of the actin cytoskeleton plays an important role in the invasion and migration of HCC cells. In previous studies, we found that CAPZA1, a capping protein, can promote EMT of HCC cells by regulating the remodeling of the actin filament (F-actin) cytoskeleton, thus promoting the invasion and migration of HCC cells. In this study, we found that FAM21C may have a regulatory effect on CAPZA1, and we conducted an in-depth study on its potential regulatory mechanism. First, we found that FAM21C is highly expressed in HCC tissues and its high expression could promote the malignant progression of HCC. Meanwhile, the high expression of FAM21C promoted the invasion and migration of HCC cells in vitro and in vivo. Further, FAM21C interacted with CAPZA1, and their binding inhibited the capping capacity of CAPZA1, thus promoting the invasion and migration of HCC cells. This effect of FAM21C was abolished by mutating the CP-interacting (CPI) domain, the CAPZA1 binding site on FAM21C. In conclusion, high expression of FAM21C in HCC tissues can promote malignant progression of HCC and its potential mechanism involves FAM21C inhibition of CAPZA1 capping capacity by binding to CAPZA1, which drives F-actin cytoskeleton remodeling, and thus promotes invasion and migration of HCC cells.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common tumor in the world and the second leading cause of cancer-related deaths [1], and its high malignancy poses a serious threat to human health
FAM21C expression was up-regulated in HCC tissues and its high expression was significantly associated with malignant progression of HCC
We found and confirmed that FAM21C could interact with CAPZA1 through its CPI domain in HCC cells and FAM21C inhibits the capping ability of CAPZA1, inducing the remodeling of the actin filament cytoskeleton, which in turn promoted HCC invasion and metastasis

Summary

Introduction

HCC is the fifth most common tumor in the world and the second leading cause of cancer-related deaths [1], and its high malignancy poses a serious threat to human health. Due to hepatitis B virus infection and aflatoxin exposure, China has become a region with the highest incidence of HCC [2]. Radical resection is still the most effective treatment for HCC, but its postoperative. The appearance of invasion- and metastasis-related phenotype, such as multifocal sites and invasion of the main vessel in HCC predicts the poor prognosis of patients [3]. It is very important to investigate the molecular mechanisms of invasion and migration of HCC cells to identify the corresponding therapeutic targets with the objective of improving the prognosis of patients

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