Hepatatis B virus X protein induces matrix metallopreteinase-9 expression via a Rac1-NADPH oxidase-reactive oxygen species-activator protein-1 pathway in human Chang liver cells

Hepatatis B virus X protein induces matrix metallopreteinase-9 expression via a Rac1-NADPH oxidase-reactive oxygen species-activator protein-1 pathway in human Chang liver cells

  In the present study, we investigated a signaling pathway that leads to expression of matrix metalloproteinase-9 (MMP-9) by HBx in human Chang liver cells. We found that HBx upregulates MMP-9 by a Rac1-NADPH oxidase-dependent pathway. Consistent with this, Rac1, if activated, was shown to stimulate MMP-9 expression in a NADPH oxidase-dependent manner. In another experiment to understand the signaling mechanism by which the Rac1-NADPH oxidase cascade mediates the induction of MMP-9 expression by HBx, we observed that HBx-induced ROS production is completely inhibited by the expression of Rac1N17 or treatment with DPI or apocynin (specific inhibitors of NADPH oxidase), suggesting that Rac1-NADPH oxidase cascade acts in this instance by producing intracellular ROS. Finally, we showed that HBx and Rac1 targets the transcription factor AP-1 to stimulate MMP-9 expression. Taken together, our findings identify a Rac1-NAD(P)H oxidase-ROS-AP-1 cascade as a novel pathway mediating HBx signaling to MMP-9 expression in liver cells.