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.
Keywords:
EBV; HIF-1α; LMP-1; Nasopharyngeal carcinoma.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
MeSH terms
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3' Untranslated Regions
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Binding Sites
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Carcinoma / genetics
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Carcinoma / metabolism*
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Carcinoma / virology
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Cell Line, Tumor
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Cell Transformation, Viral*
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Epstein-Barr Virus Infections / genetics
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Epstein-Barr Virus Infections / metabolism*
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Epstein-Barr Virus Infections / virology
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Extracellular Signal-Regulated MAP Kinases
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Gene Expression Regulation, Neoplastic
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Herpesvirus 4, Human / genetics
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Herpesvirus 4, Human / metabolism*
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Host-Pathogen Interactions
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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NF-kappa B / metabolism
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Nasopharyngeal Carcinoma
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Nasopharyngeal Neoplasms / genetics
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Nasopharyngeal Neoplasms / metabolism*
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Nasopharyngeal Neoplasms / virology
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RNA Stability
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Time Factors
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Transcription, Genetic
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Transfection
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Tristetraprolin / genetics
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Tristetraprolin / metabolism
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Up-Regulation
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Viral Matrix Proteins / genetics
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Viral Matrix Proteins / metabolism*
Substances
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3' Untranslated Regions
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EBV-associated membrane antigen, Epstein-Barr virus
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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NF-kappa B
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PUM2 protein, human
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RNA, Messenger
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RNA-Binding Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Tristetraprolin
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Viral Matrix Proteins
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ZFP36 protein, human
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Extracellular Signal-Regulated MAP Kinases