Evaluation of Nuclear Factor-κB, Urokinase-Type Plasminogen Activator, and HBx and Their Clinicopathological Significance in Hepatocellular Carcinoma

Abstract

Purpose: Nuclear factor B (NF-B) 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-B 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-B 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-B signaling pathway and uPA up-regulation mediated by HBx were also analyzed in vitro.Results: We found that NF-B activation and uPA upregulation were frequently (56% and 59%, respectively) observed in HCCs, and particularly in HBx-positive HCCs. NF-B activation and uPA overexpression were closely associated with one another (P < 0.0001). Furthermore, both activation of NF-B 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-B activation was induced by HBx transfection in HepG2 cells through inhibitor of nuclear factor-B kinase ␤ (IKK␤). HBx also up-regulated uPA and enhanced cell invasion synergistically with IKK␤.Conclusions: The data indicate that NF-B dysregulation and uPA overexpression may lead to a more aggressive tumor behavior in HCC. In addition, our data suggest that IKK␤ plays a critical role in the HBx-activated NF-B signaling pathway.

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

“…The first evidence implicating NF-B activation mediated pathogen-induced carcinogenesis was identification of the REV-T viral oncogene that causes avian reticuloendothelial lymphomatosis, v-Rel, which shares a Rel transactivation domain with the mammalian homologues NF-family members (47). Hepatitis B X protein and hepatitis C 5A and core proteins have been shown to activate NF-B and are implicated in carcinogenesis of hepatocellular carcinoma (48). In addition, the specific subtypes of human papillomavirus (HPV) infection are potentially oncogenic in the uterine cervix, vagina, vulva, anus, penis, skin, and oropharynx (49,50).…”

Nuclear factor‐κB and the hepatic inflammation‐fibrosis‐cancer axis†

“…Furthermore, the oncogenic HBV protein HBx and the HCV core and NS5B proteins were reported to induce NF-B. [29][30][31] The natural conclusion from these observations was that NF-B operates as a tumor promoter in virus-infected or transformed hepatocytes.…”

NF‐κB in liver diseases: a target for drug therapy

“…Several in vitro studies utilizing human HCC cell lines have shown that NF-κB is cytoprotective by means of preventing apoptosis. In addition, the oncogenic HBV protein HBx and the HCV core were reported to induce NF-κB activation (Chan et al, 2004;Arsura and Cavin, 2005). Loss of NF-κB activity in parenchymal cells may actually promote tumor development.…”