Original ArticlecPLA2α activates PI3K/AKT and inhibits Smad2/3 during epithelial-mesenchymal transition of hepatocellular carcinoma cells

- High cPLA2α expression was linked to microvascular HCC invasion, spatial distribution, and lower survival.
- cPLA2α played an important role in HCC proliferation, migration, and invasion.
- cPLA2α mediated EGF-induced EMT through the PI3K/AKT/ERK pathway.
- cPLA2α mediated TGF-β-induced EMT by inhibiting Smad2/3 phosphorylation and promoting PI3K/AKT/ERK phosphorylation.

Cytosolic phospholipase A2α (cPLA2α), a key phospholipase that regulates lipid metabolism, plays an important role in tumor progression. In the present study of hepatocellular carcinoma (HCC), cPLA2α was overexpressed in highly metastatic HCC cell lines. Immunohistochemical staining showed increased levels of cPLA2α 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 cPLA2α inhibited migration, probably due to its role in actin polymerization. Overexpression of cPLA2α promoted cell migration and invasion. Based on the mechanistic analysis, our data suggested that cPLA2α mediate epidermal growth factor (EGF) induced epithelial-mesenchymal transition (EMT) through PI3K/AKT/ERK pathway. cPLA2α activity was required for the transforming growth factor-(TGF)-β-induced EMT. However, cPLA2α inhibited Smad2/3 activation and promoted the activation of the PI3K/AKT/ERK pathway. A xenograft tumor transplant model confirmed the role of cPLA2α in HCC invasion and metastasis. Based on the mechanistic analysis, cPLA2α mediated both EGF- and TGF-β-induced EMT, which are essential for HCC metastasis. cPLA2α is a potentially target for novel therapies of HCC.