title: Hepatitis B virus X protein inhibits p53-mediated upregulation of mitofusin-2 in hepatocellular carcinoma cells.
abstract: The hepatitis B virus X (HBx) protein has many significant roles in hepatocellular carcinoma (HCC). Our previous research demonstrated that mitofusion-2 (Mfn2), a potential tumor suppressor gene in HCC, is a novel direct target of p53 that exerts apoptotic effects via the mitochondrial apoptotic pathway. However, the relationship between HBx and Mfn2 expression in the development of HCC is unknown. We found that HBx had little direct effect on the expression of Mfn2 or p53 in HCC cells not treated with doxorubicin. However, HBx inhibited the upregulation of Mfn2 in HBx-transfected HCC cells simultaneously treated with doxorubicin or cotransfected with p53 plasmid, as evidenced by Western Blot and real-time PCR. Through electrophoretic mobility shift analysis, we confirmed that HBx interfered with the binding event of the p53 protein and the p53 binding site-oligo of the Mfn2 promoter. Moreover, luciferase assays revealed that the activity of the Mfn2 promoter did not increase when transfected with HBx plasmid in doxorubicin-treated HepG2 cells. These results indicate that HBx impacts p53-mediated transcription of Mfn2, providing insight into the negative effect of HBx against p53-dependent chemotherapeutic agents, such as doxorubicin, used in the treatment of HCC.
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, PR China.
authors.forename: Weilin
authors.initials: W
authors.lastname: Wang
authors.forename: Dongkai
authors.initials: D
authors.lastname: Zhou
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wei
authors.forename: Zehui
authors.initials: Z
authors.lastname: Wu
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Cheng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Sun
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D000903:Antibiotics, Antineoplastic; D024101:Mitochondrial Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D004317:Doxorubicin; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human