Evaluation of nuclear factor-κB, urokinase-type plasminogen activator, and HBx and their clinicopathological significance in hepatocellular carcinoma

Purpose: Nuclear factor kappaB (NF-kappaB) signaling pathway is an important regulating pathway in human diseases and cancers. One of its downstream target genes is urokinase plasminogen activator (uPA), which is involved in cancer invasion and metastasis. The purpose of this study was to evaluate NF-kappaB activation, uPA up-regulation, and hepatitis B viral X protein (HBx) expression in human hepatocellular carcinoma (HCC) and to assess their clinicopathological significance. Experimental Design: We evaluated NF-kappaB activation, expression of uPA, and presence of HBx in 32 human HCCs. Their clinicopathological significance was assessed by correlation with the clinicopathological features. Aberrant NF-kappaB signaling pathway and uPA up-regulation mediated by HBx were also analyzed in vitro. Results: We found that NF-kappaB activation and uPA up-regulation were frequently (56% and 59%, respectively) observed in HCCs, and particularly in HBx-positive HCCs. NF-kappaB activation and uPA overexpression were closely associated with one another (P < 0.0001). Furthermore, both activation of NF-kappaB and up-regulation of uPA were significantly associated with a more aggressive tumor behavior in terms of venous invasion, direct liver invasion, and absence of tumor encapsulation. In vitro, NF-kappaB activation was induced by HBx transfection in HepG2 cells through inhibitor of nuclear factor-kappaB kinase beta (IKKbeta). HBx also up-regulated uPA and enhanced cell invasion synergistically with IKKbeta. Conclusions: The data indicate that NF-kappaB dysregulation and uPA overexpression may lead to a more aggressive tumor behavior in HCC. In addition, our data suggest that IKKbeta plays a critical role in the HBx-activated NF-kappaB signaling pathway.