Crosstalk between Beta-Catenin and Snail in the Induction of Epithelial to Mesenchymal Transition in Hepatocarcinoma: Role of the ERK1/2 Pathway

Nathalie Zucchini-Pascal,Ludovic Peyre,Roger Rahmani

doi:10.3390/ijms141020768

Abstract

Epithelial to mesenchymal transition (EMT) is an integral process in the progression of many epithelial tumors. It involves a coordinated series of events, leading to the loss of epithelial features and the acquisition of a mesenchymal phenotype, resulting in invasion and metastasis. The EMT of hepatocellular carcinoma (HCC) cells is thought to be a key event in intrahepatic dissemination and distal metastasis. In this study, we used 12-O-tet-radecanoylphorbol-13-acetate (TPA) to dissect the signaling pathways involved in the EMT of HepG2 hepatocarcinoma cells. The spectacular change in phenotype induced by TPA, leading to a pronounced spindle-shaped fibroblast-like cell morphology, required ERK1/2 activation. This ERK1/2-dependent EMT process was characterized by a loss of E-cadherin function, modification of the cytoskeleton, the acquisition of mesenchymal markers and profound changes to extracellular matrix composition and mobility. Snail was essential for E-cadherin repression, but was not sufficient for full commitment of the TPA-triggered EMT. We found that TPA triggered the formation of a complex between Snail and β-catenin that activated the Wnt pathway. This study thus provides the first evidence for the existence of a complex network governed by the ERK1/2 signaling pathway, converging on the coregulation of Snail and the Wnt/β-catenin pathway and responsible for the onset and the progression of EMT in hepatocellular carcinoma cells.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed, and the third most deadly, cancer worldwide [1,2]
We studied the kinetics of MAPK activation in HepG2 cells by western blotting with antibodies directed against phosphorylated forms of ERK1/2, p38 and Jun N-terminal protein kinases (JNKs), to analyze kinase activation
TPA treatment led to a considerable increase in the amounts of phosphorylated forms of ERK1/2 and their known downstream effectors (Figure 1A)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed, and the third most deadly, cancer worldwide [1,2]. The escape of carcinoma cells from the solid tumor may result from the dedifferentiation of epithelial cells, through a loss of cell-to-cell contact accompanied by an increase in migratory and invasive capacities [7]. This phenotypic conversion, collectively referred to as the epithelial to mesenchymal transition (EMT), is considered to constitute an important process in intrahepatic dissemination and distal metastasis during HCC progression [8,9]. Additional cell-to-cell junctions (adherens and gap junctions) are disrupted and the underlying basement membrane is broken down [13]. Cell surface proteins, such as E-cadherin and integrins, responsible for connecting epithelial cells to neighboring cells and to the basement membrane, respectively, are replaced by

Results

Discussion

Conclusion