The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression.
Hepatocellular carcinoma is strongly associated with chronic infection by the hepatitis B virus (HBV) and has poor prognosis due to intrahepatic metastasis. HBx is often the only HBV protein detected in hepatic tumor cells; however, its contribution to tumor invasion and metastasis has not been established so far. In this work, we show that HBx enhances tumor cell invasion, both in vivo and in vitro. The increased invasive capacity induced by HBx is mediated by an upregulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) expression, which in turn activates matrix metalloproteinase-2. Induction of both MT1-MMP expression and cell invasion by HBx is dependent on cyclooxygenase-2 (COX-2) activity. In addition, HBx upregulates the expression of COX-2, which is mediated by the transcriptional activation of the COX-2 gene promoter in a nuclear factor of activated T cell-dependent (NF-AT-dependent) manner. These results demonstrate the ability of HBx to promote tumor cell invasion by a mechanism involving the upregulation of MT1-MMP and COX-2 and provide new insights into the mechanism of action of this viral protein and its involvement in tumor metastasis and recurrence of hepatocellular carcinoma.
Lara-Pezzi
Enrique
E
Unidad de Biología Molecular, Hospital Universitario de la Princesa, Madrid, Spain.
Gómez-Gaviro
Maria Victoria
MV
Gálvez
Beatriz G
BG
Mira
Emilia
E
Iñiguez
Miguel A
MA
Fresno
Manuel
M
Martínez-A
Carlos
C
Arroyo
Alicia G
AG
López-Cabrera
Manuel
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D002642:Chick Embryo; D016895:Culture Media, Serum-Free; D051546:Cyclooxygenase 2; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006511:Hepatitis B Antigens / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008565:Membrane Proteins; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology; D054334:Viral Regulatory and Accessory Proteins
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D006511:Hepatitis B Antigens; D007527:Isoenzymes; D008565:Membrane Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2