title: Positive regulation of HIF-1A expression by EBV oncoprotein LMP1 in nasopharyngeal carcinoma cells.
abstract: Latent membrane protein 1 (LMP1) is a pivotal viral oncoprotein that contributes to the carcinogenesis of Epstein-Barr virus (EBV)-associated malignancies, including nasopharyngeal carcinoma (NPC). We investigated the regulation of hypoxia-inducible factor 1-α (HIF-1α) by LMP1. In NPC cells, we found that LMP1 significantly enhanced the HIF-1α mRNA level, and not only the protein amount as described previously. Mechanistically, the stability of the HIF-1α transcript was remarkably prolonged by LMP1 via reduced expressions of RNA-destabilizing proteins tristetraprolin (TTP) and pumilio RNA-binding family member 2 (PUM2) through C-terminal activation region 1 (CTAR1) and CTAR3 interaction with the ERK1/2 and STAT3 signaling pathways, respectively, in parallel with hindrance of PUM2 binding to the HIF-1α mRNA 3'-untranslated region (3'-UTR). On the other hand, HIF-1A promoter activity was also obviously facilitated by the LMP1 CTAR1-recruited ERK1/2/NF-κB pathway. Intriguingly, in this scenario, augmented HIF-1α further exhibited positive auto-regulation of its own gene transcription. Our results showed the first time that LMP1 directly up-regulates HIF-1A transcription and post-transcription in NPC cells, in addition to providing evidence of an increase in the HIF-1α mRNA level caused by a tumor-associated virus under normoxic conditions.
authors: Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan.
authors: Wei-Wen
authors: WW
authors: Sung
authors: Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan.
authors: Yi-Chih
authors: YC
authors: Chu
authors: Department of Otolaryngology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
authors: Peir-Rong
authors: PR
authors: Chen
authors: Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan. Electronic address: mhliao@mail.npust.edu.tw.
authors: Ming-Hui
authors: MH
authors: Liao
authors: Department of Life Sciences, Tzu-Chi University, Hualien, Taiwan; Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan. Electronic address: jwlee@mail.tcu.edu.tw.
authors: Jeng-Woei
authors: JW
authors: Lee
mesh_terms: D020413:3' Untranslated Regions; D001665:Binding Sites; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D048049:Extracellular Signal-Regulated MAP Kinases; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; C471243:PUM2 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051816:Tristetraprolin; D014763:Viral Matrix Proteins; C497552:ZFP36 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: EBV; HIF-1α; LMP-1; Nasopharyngeal carcinoma