Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential.
Hepatitis B virus (HBV) X protein (HBx) has been shown to be essential for the development of hepatocellular carcinoma (HCC). Recently, we have found that HBx causes the progression of liver cancer through down-expression of PTEN, known as a tumor suppressor gene (1). The prognosis for HCC depends mainly on the clinicopathological characteristic regarding invasion and metastasis. The expression of matrix metalloproteinase (MMP)-9 has been implicated as playing an important role in HCC invasion and metastasis. We previously reported that HBV infection increased the invasiveness of hepatocytes and HCC cells through the transcriptional activation of MMP-9 (2). The HBx was shown to activate the mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI-3K) signal cascade, which is essential for activation of transcription factors such as activating protein (AP)-1 and nuclear factor (NF)-kappaB. In this study, we show that the HBx protein stimulates the activities of the PI-3K-Akt/ protein kinase B (PKB) as well as extracellular signal-regulated kinase 1/2 (ERK 1/2) in HBx-transfected cells. Furthermore, we have shown that enhanced expression of MMP-9 in HBx-transfected cells mediated by not only activation of AP-1 transcriptional activity through ERKs pathway but also activation of NF-kappaB transcriptional activity through PI-3K-AKT/PKB pathway, and was associated with the invasive potential. However, treatment with U0126 (known as the ERKs inhibitor) or wortmannin (known as the PI-3K inhibitor), but not SB203580 (known as the p38 MAPK inhibitor), markedly inhibited the expression of MMP-9 induced by HBx in HBx-transfected cells. Seemingly, the invasiveness of HBx-transfected cells was decreased by treating with U0126 or wortmannin, but not SB203580. These results clearly suggest that the HBx contributed to the transcriptional regulation of MMP-9 through the ERKs and PI-3K-AKT/PKB pathway, and increased an invasive potential of cells.
Chung
Tae-Wook
TW
National Research Laboratories for Glycobiology, Ministry of Science and Technolgoy, and Department of Biochemistry and Molecular Biology, College of Oriental Medicine, Dongguk University, Kyungju, South Korea.
Lee
Young-Choon
YC
Kim
Cheorl-Ho
CH
D000730:Androstadienes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000201:enzymology / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins; D000077191:Wortmannin
D000730:Androstadienes; D002070:Butadienes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016328:NF-kappa B; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D000077191:Wortmannin; C113580:U 0126; C057628:hepatitis B virus X protein; C494918:AKT1 protein, human; C093642:SB 203580