Hepatitis B virus X protein promotes tumor invasion and poor prognosis in hepatocellular carcinoma via phosphorylation of paxillin at Serine 178 by activation of the c-Jun NH2-terminal kinase.

Hepatitis B virus X protein (HBx) plays critical roles in hepatocellular tumorigenesis by activating different signaling pathways, including the c-Jun NH2-terminal kinase (JNK) pathway. Phosphorylation of paxillin (PXN) promotes cell migration via activation of the JNK signaling pathway, but PXN overexpression is not associated with poor outcome in patients with hepatocellular carcinoma (HCC). HBx gene manipulation and Western blotting indicated that phosphorylation of PXN at Serine 178 (p(S178)-PXN) by HBx may promote invasiveness in HCC cells via HBx-mediated JNK activation. Immunohistochemical analysis indicated a positive correlation between p(S178)-PXN and HBx expression levels in tumor specimens. The overall survival (OS) and relapse-free survival (RFS) were poorer in patients with high-p(S178)-PXN expressing or high-HBx expressing tumors than in patients with low-p(S178)-PXN expressing or low-HBx expressing tumors. In conclusion, phosphorylation of PXN at Serine 178 by HBx-mediated JNK activation may therefore play a critical role in tumor invasiveness and poor prognosis in patients with HBV-infected hepatocellular tumors. The expression levels of p(S178)-PXN may be a reliable prognostic biomarker to predict the clinical outcomes in patients with HBV-associated HCC.