title: HBx interacted with Smad4 to deprive activin a growth inhibition function in hepatocyte HL7702 on CRM1 manner.
abstract: Hepatitis B virus (HBV) is implicated in the pathogenesis of hepatocellular carcinoma, which has been found to be associated with TGF-beta signaling. Activin A is a TGF-β family cytokine that exhibits cell proliferation inhibition on normal hepatocyte. How HBV-encoded X oncoprotein play in activin's activity on hepatocyte has not been developed. In this study, a nontumor hepatic cell line HL7702 with HBX ectogenic expression has been established. MTT and BrdU assays showed that HBx promoted growth of HL7702 cells in vitro and downregulated activin signaling. Deregulated activin signaling pathway by HBX failed to activate target gene p21/waf1 and p15 transcription. In addition, mammalian two-hybrid and coimmunoprecipitation assays revealed that HBX could directly interact with activin signaling transduction protein Smad4, making activated Smad2/3/4 nucleus translocation suppressed. Furthermore, we detected that leptomycin B, the inhibitor of CRM1 protein, could recover nuclear translocation of endogenous Smads complex in HL7702 with HBX expression, indicating that HBX antagonized Smads nucleus translocation, at least partially, on CRM1-dependent manner. Leptomycin B was found to have antigrowth activity on HBX-expressed HL7702, according to its antitumor function in previous study. Above all, HBX antagonized activin signaling in normal human liver cells by interacting with Smad4 might one of the considerable causes of HBX-induced hepatocyte transformation, which deprived activin's cell growth inhibition function at an early stage of tumorigenesis.
authors.affiliation: Institute of Translational Medicine, First Hospital of Jilin University, Changchun, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: The First Clinical Medical College of Jilin University, Changchun, People's Republic of China.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Translational Medicine, First Hospital of Jilin University, Changchun, People's Republic of China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Han
authors.affiliation: Tumor Biological Treatment Center of Jilin Province People's Hospital, Changchun, People's Republic of China.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Mi
authors.affiliation: Institute of Translational Medicine, First Hospital of Jilin University, Changchun, People's Republic of China. zhangwenyan@jlu.edu.cn.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Institute of Translational Medicine, First Hospital of Jilin University, Changchun, People's Republic of China. mingyulv@jlu.edu.cn.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Lv
mesh_terms: D021581:Active Transport, Cell Nucleus; D028341:Activins / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D028884:Karyopherins / Q000502:physiology*; D008113:Liver Neoplasms / Q000209:etiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D051901:Smad4 Protein / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins; D000097606:Exportin 1 Protein
chemical_list: D028341:Activins; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D051901:Smad4 Protein; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D000097606:Exportin 1 Protein; C497796:SMAD4 protein, human; C057628:hepatitis B virus X protein