cPLA2α activates PI3K/AKT and inhibits Smad2/3 during epithelial-mesenchymal transition of hepatocellular carcinoma cells

Cytosolic phospholipase A2 alpha (cPLA2 alpha), a key phospholipase that regulates lipid metabolism, plays an important role in tumor progression. In the present study of hepatocellular carcinoma (HCC), cPLA2 alpha was overexpressed in highly metastatic HCC cell lines. Immunohistochemical staining showed increased levels of cPLA2 alpha at the invasive edges of HCC, and a clinicopathological analysis of samples from 111 patients revealed that its expression level was linked with micro-vascular invasion and cirrhosis. Knockdown of cPLA2 alpha inhibited migration, probably due to its role in actin polymerization. Overexpression of cPLA2 alpha promoted cell migration and invasion. Based on the mechanistic analysis, our data suggested that cPLA2 alpha mediate epidermal growth factor (EGF) induced epithelial-mesenchymal transition (EMT) through PI3K/AKT/ERK pathway. cPLA2 alpha activity was required for the transforming growth factor-(TGF)-beta-induced EMT. However, cPLA2 alpha inhibited Smad2/3 activation and promoted the activation of the PI3K/AKT/ERK pathway. A xenograft tumor transplant model confirmed the role of cPLA2 alpha in HCC invasion and metastasis. Based on the mechanistic analysis, cPLA2 alpha mediated both EGF- and TGF-beta-induced EMT, which are essential for HCC metastasis. cPLA2 alpha is a potentially target for novel therapies of HCC. (C) 2017 Elsevier B.V. All rights reserved.