title: Nuclear IKKα mediates microRNA-7/-103/107/21 inductions to downregulate maspin expression in response to HBx overexpression.
abstract: Maspin is a tumor suppressor that stimulates apoptosis and inhibits metastasis in various cancer types, including hepatocellular carcinoma (HCC). Our previous study has demonstrated that HBx induced microRNA-7, 103, 107, and 21 expressions to suppress maspin expression, leading to metastasis, chemoresistance, and poor prognosis in HCC patients. However, it remains unclear how HBx elicits these microRNA expressions. HBx has been known to induce aberrant activation and nuclear translocation of inhibitor-κB kinase-α (IKKα) to promote HCC progression. In this study, our data further revealed that nuclear IKKα expression was inversely correlated with maspin expression in HBV-associated patients. Nuclear IKKα but not IKKβ reduced maspin protein and mRNA expression, and inhibition of IKKα reverses HBx-mediated maspin downregulation and chemoresistance. In response to HBx overexpression, nuclear IKKα was further demonstrated to induce the gene expressions of microRNA-7, -103, -107, and -21 by directly targeting their promoters, thereby leading to maspin downregulation. These findings indicated nuclear IKKα as a critical regulator for HBx-mediated microRNA induction and maspin suppression, and suggest IKKα as a promising target to improve the therapeutic outcome of HCC patients.
authors.affiliation: Department of Pharmacology, National Taiwan University, Taipei, Taiwan.|Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors.forename: Wen-Shu
authors.initials: WS
authors.lastname: Chen
authors.affiliation: Division of Breast Surgery, Department of Surgery, China Medical University Hospital, Taichung, Taiwan.|School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Liang-Chih
authors.initials: LC
authors.lastname: Liu
authors.affiliation: Internal Medicine, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan.|Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Yun-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.|The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan.
authors.forename: Jhen-Yu
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chien-Yi
authors.initials: CY
authors.lastname: Ho
authors.affiliation: Department of Health Care and Social Work, Yu Da University of Science and Technology, Miaoli, Taiwan.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, National Taiwan University, Taipei, Taiwan.
authors.forename: Ching-Chow
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.|The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Huang
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006515:Hepatitis B virus / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000821:virology; D035683:MicroRNAs / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D035683:MicroRNAs; D012333:RNA, Messenger; C085344:SERPIN-B5; D015843:Serpins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human
keywords: HBx; IKKα; hepatocellular carcinoma; maspin; microRNA