Abstract
Tumor necrosis factor α-induced protein 3 (A20) suppresses inflammation by inhibiting the activation of nuclear factor kappa B (NF-κB). The aberrant expression of A20 is reportedly correlated with tumor development in human malignancies, including hepatocellular carcinoma (HCC). Proinflammatory mediators, including tumor necrosis factor α (TNF-α), interleukin-1, and lipopolysaccharide, may induce A20 expression. The present study revealed that epidermal growth factor (EGF) significantly increased A20 mRNA and protein levels in normal hepatic and hepatoma cells via the mitogen-activated protein kinase kinase-1 (MEK1)/mitogen- and stress-activated protein kinase-1 (MSK1)/phosphorylated (p)-p65 (Ser276) signaling pathway. A significant positive correlation was observed between the expression of EGF receptor and A20 in HCC and normal healthy liver tissues. The EGF-induced A20 upregulation was NF-κB-dependent and abolished by either the overexpression of the nuclear factor of a κ light polypeptide gene enhancer in a B-cell inhibitor α or treatment with the NF-κB inhibitor BAY11-7082. However, unlike TNF-α, EGF expression did not result in the upregulation of inflammatory molecules, including intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and monocyte chemoattractant protein-1. These results indicate that EGF preferentially upregulated the protective mediator A20 over proinflammatory factors. To our knowledge, the present study is the first to demonstrate that EGF induced A20 expression by activating the MEK1/MSK1/p-p65 (Ser276) signaling pathway without causing an apparent inflammatory response. These results may further extend our understanding of liver inflammation and tumor development.