title: Alpha fetoprotein mediates HBx induced carcinogenesis in the hepatocyte cytoplasm.
abstract: Although tumor-associated fetal protein AFP has demonstrated utility as a clinical tumor marker, the significance of intracellular AFP is still unclear. The aim of this study was to explore the role of cytoplasmic AFP during HBx induced carcinogenesis, which had not previously been recognized; 614 HCC patients were analyzed for correlation of HBV infection with AFP level, and much higher AFP levels were found in HBsAg positive patients. Tumor tissue specimens from 20 HCC patients were used for analysis of AFP and GADD45α. Analysis of HCC specimens showed that upregulation of cytoplasmic AFP is associated with down-regulation of GADD45α in neoplastic tissue. Transfected HBx promotes transcription of AFP by acting on the elements in the AFP gene regulatory region. HBx itself did not directly impact transcription of GADD45α. However, the obstruction of RAR signaling by HBx induced elevation of AFP, which led to down-regulation of GADD45α. Cytoplasmic AFP was able to interact with RAR, disrupting its entrance into the nucleus and binding to the elements in the regulatory region of the GADD45α gene. Knockdown of AFP in siRNA-transfected AFP positive cell lines was synchronously associated with an incremental increase of RAR binding to DNA, as well as upregulation of GADD45α and it was contrary in AFP gene-transfected AFP negative cell lines. These results indicate cytoplasmic AFP is not only a histochemical tumor biomarker for human hepatoma but is also an intracellular signal molecule and potential participant in HBx induced hepatocarcinogenesis.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Beijing You'an Hospital, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McNutt
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Fengmin
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.|Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; D000509:alpha-Fetoproteins; C097353:AFP protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins
keywords: HBV; all trans retinoic acid; alpha fetoprotein; carcinogenesis; growth arrest and DNA damage 45α; nuclear receptor