Tenascin-C expression is associated with poor prognosis in hepatocellular carcinoma (HCC) patients and the inflammatory cytokine TNF-α-induced TNC expression promotes migration in HCC cells

Although tenascin-c (TNC) in inflammatory microenvironment contributes to progression in some tumors, its role in hepatocellular carcinoma (HCC) in metastasis and the mechanism by which TNC expression is regulated in HCC cells are elusive. In this study, we examined TNC expression in 100 HCC tissue samples by immunohistochemistry and compared which between the groups with or without metastasis. TNC expression was higher in metastatic HCC tissues than that in the non-metastatic HCC tissues, which was associated with the Knodell inflammation scores. Importantly, high level of TNC expression was associated with lower survival rate and shorter survival time in the HCC patients. We then investigated the mechanism by which TNC expression is regulated in HCC cells with an in vitro cell culture system. The recombinant TNF-alpha and conditioned medium from macrophages induced TNC expression at both mRNA and protein levels in HepG2 cells. The induction of TNC expression by conditioned medium from macrophages was suppressed by a TNF-alpha neutralizing antibody. TNF-alpha-promoted cell migration was inhibited by a TNC siRNA. In addition, TNF-alpha-induced TNC expression was blocked by a NF-kappa B pathway inhibitor. These results suggest that TNF-alpha in the tumor microenvironment induces TNC expression in HCC cells through the NF-kappa B pathway, which in turn, promotes HCC cell migration. Thus, TNC may play an important role in promoting HCC metastasis and TNC expression could be a predictive factor for poor prognosis in HCC patients.