The Role of NF-κB in Hepatitis B Virus X Protein-Mediated Upregulation of VEGF and MMPs

ABSTRACT

Hepatitis B virus X protein (HBx) promotes hepatocellular carcinoma (HCC) invasion and metastasis by a poorly understood mechanism. This study investigated the role of NF-κ B in HBx-mediated upregulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). In a stably expressing HBx cell line, NF-κ B level was examined by laser scanning confocal microscopy before and after treatment with pyrrolidine dithiocarbamate (PDTC; an NF-κ B inhibitor). VEGF, MMP2, MMP9, and MMP14 mRNA and protein levels were quantitated by real-time PCR and Western blotting, respectively. HBx stimulated NF-κ B signaling and increased VEGF, MMP2, MMP9, and MMP14 mRNA and protein levels. PDTC treatment blocked HBx-mediated stimulation of NF-κ B signaling and decreased VEGF, MMP9, and MMP14 (but not MMP2) mRNA and protein levels. In vivo studies, PDTC reduced angiogenesis in subcutaneous xenograft of nude mice which injected HepG2-HBx cells. This suggests that NF-κ B is involved in upregulating these genes and in the HBx-mediated invasion and metastasis of HCC.

Keywords: :

• Carcinogenesis
• Invesion & metastais
• Tumor cell biology
• Liver & billary system cancer

ACKNOWLEDGMENTS

This work was supported by grants from the Key Project of National Natural Science Foundation of China (Grant No: 30430670), the Chinese Ministry of Public Health for Key Clinical Projects (Grant No: 353 [2007]), and Hepatic Surgery Medical Clinical Research Centre of Hubei, China (2007).

Declaration of interest: The authors report no conflicts of interest. The authors are responsible for the content and writing of the paper.

These authors contributed equally to this work.