title: Doxorubicin Activates Hepatitis B Virus Replication by Elevation of p21 (Waf1/Cip1) and C/EBPα Expression.
abstract: Hepatitis B virus reactivation is an important medical issue in cancer patients who undergo systemic chemotherapy. Up to half of CHB carriers receiving chemotherapy develop hepatitis and among these cases a notable proportion are associated with HBV reactivation. However, the molecular mechanism(s) through which various chemotherapeutic agents induce HBV reactivation is not yet fully understood. In this study, we investigated the role of the cell cycle regulator p21 (Waf1/Cip1) in the modulation of HBV replication when a common chemotherapeutic agent, doxorubicin, is present. We showed that p21 expression was increased by doxorubicin treatment. This elevation in p21 expression enhanced the expression of CCAAT/enhancer-binding protein α (C/EBPα); such an increase is likely to promote the binding of C/EBPα to the HBV promoter, which will contribute to the activation of HBV replication. Our current study thus reveals the mechanism underlying doxorubicin modulation of HBV replication and provides an increased understanding of HBV reactivation in CHB patients who are receiving systemic chemotherapy.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Faculty of Traditional Chinese Medicine, Southern University College, Johor Bahru, Malaysia.
authors.forename: Chin-Liew
authors.initials: CL
authors.lastname: Chong
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Wu
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan; Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Kuen-Nan
authors.initials: KN
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Tzer-Min
authors.initials: TM
authors.lastname: Kuo
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ming-Hsiang
authors.initials: MH
authors.lastname: Hong
authors.affiliation: Department of Life Science, Tunghai University, Taichung, Taiwan.
authors.forename: Cheng-Po
authors.initials: CP
authors.lastname: Hu
authors.affiliation: Center for Molecular Medicine, China Medical University and Hospital, Taichung, Taiwan.
authors.forename: Mong-Liang
authors.initials: ML
authors.lastname: Chen
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Chou
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Chungming
authors.initials: C
authors.lastname: Chang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012367:RNA, Viral; D020218:Response Elements; D014775:Virus Activation / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000903:Antibiotics, Antineoplastic; D022763:CCAAT-Enhancer-Binding Protein-alpha; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012367:RNA, Viral; D004317:Doxorubicin