title: C-terminal-truncated HBV X promotes hepato-oncogenesis through inhibition of tumor-suppressive β-catenin/BAMBI signaling.
abstract: C-terminal-truncated hepatitis B virus (HBV) X (HBx) (ctHBX) is frequently detected in hepatocellular carcinoma (HCC) through HBV integration into the host genome. However, the molecular mechanisms underlying ctHBx-associated oncogenic signaling have not yet been clarified. To elucidate the biological role of ctHBx in hepato-oncogenesis, we functionally analyzed ctHBx-mediated regulation of the activin membrane-bound inhibitor bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) through transforming growth factor-β (TGF-β) or β-catenin (CTNNB1) in HCC cells and in an animal model, and we compared its role to that of the full-length HBx protein. Ectopic ctHBx expression generated more colonies in anchorage-dependent and -independent growth assays than did HBx expression alone. ctHBx downregulated BAMBI to a greater degree than did HBx in HCC cells. HBx activated the Wnt/β-catenin pathway, which positively regulated the BAMBI expression through T-cell factor 1 signaling, whereas ctHBx negatively regulated the Wnt/β-catenin pathway. BAMBI downregulated the β-catenin and TGF-β1 signaling pathways. TGF-β1 positively regulated BAMBI expression thorough Smad3 signaling. Furthermore, knockdown of BAMBI was more tumorigenic in HCC cells. Therefore, downregulation of both β-catenin and TGF-β1 signaling by BAMBI might contribute to tumor suppression in mice xenotransplanted with HepG2 or SH-J1 cells. Taken together, ctHBx may have a more oncogenic role than HBx through its inhibition of tumor-suppressive β-catenin/BAMBI signaling.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine of Chonbuk National University, Jeonju, Jeonbuk, Republic of Korea.|Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Seok
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine of Chonbuk National University, Jeonju, Jeonbuk, Republic of Korea.|Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine of Chonbuk National University, Jeonju, Jeonbuk, Republic of Korea.|Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine of Chonbuk National University, Jeonju, Jeonbuk, Republic of Korea.|Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Goung-Ran
authors.initials: GR
authors.lastname: Yu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine of Chonbuk National University, Jeonju, Jeonbuk, Republic of Korea.|Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Dae-Ghon
authors.initials: DG
authors.lastname: Kim
mesh_terms: D000818:Animals; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C485671:BAMBI protein, human; D008565:Membrane Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin; C057628:hepatitis B virus X protein