title: ER stress negatively modulates the expression of the miR-199a/214 cluster to regulates tumor survival and progression in human hepatocellular cancer.
abstract: BACKGROUND
  Recent studies have emphasized causative links between microRNAs (miRNAs) deregulation and tumor development. In hepatocellular carcinoma (HCC), more and more miRNAs were identified as diagnostic and prognostic cancer biomarkers, as well as additional therapeutic tools. This study aimed to investigate the functional significance and regulatory mechanism of the miR-199a2/214 cluster in HCC progression.
  
  
  RESULTS
  In this study, we showed that miR-214, as well as miR-199a-3p and miR-199a-5p levels were significantly reduced in the majority of examined 23 HCC tissues and HepG2 and SMMC-7721 cell lines, compared with their nontumor counterparts. To further explore the role of miR-214 in hepatocarcinogenesis, we disclosed that the ER stress-induced pro-survival factor XBP-1 is a target of miR-214 by using western blot assay and luciferase reporter assay. Re-expression of miR-214 in HCC cell lines (HepG2 and SMMC-7721) inhibited proliferation and induced apoptosis. Furthermore, ectopic expression of miR-214 dramatically suppressed the ability of HCC cells to form colonies in vitro and to develop tumors in a subcutaneous xenotransplantation model of the BALB/c athymic nude mice. Moreover, reintroduction of XBP-1s attenuated miR-214-mediated suppression of HCC cells proliferation, colony and tumor formation. To further understand the mechanism of the miR-199a/214 cluster down-expression in HCC, we found that thapsigargin (TG) and tunicamycin (TM) or hypoxia-induced unfolded protein response (UPR) suppresses the expression of the miR-199a/214 cluster in HCC cells. By promoter analysis of the miR-199a2/214 gene, we conjectured NFκB as a potential negative regulator. We further found that UPR and LPS-induced NFκB activation suppressed miR-199a2/214 transcription, and this suppression was reversed by NFκB inhibition in HCC cells.
  
  
  CONCLUSIONS
  Our study suggest that modulation of miR-214 levels may provide a new therapeutic approach for cancer treatment and revealed that UPR may offer a new explanation for why the miR-199a/214 cluster were down-regulated in the progression in HCC.
authors.affiliation: Department of Internal Medicine and Gene Therapy Center, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Quanlu
authors.initials: Q
authors.lastname: Duan
authors.forename: Xingxu
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Li
authors.initials: L
authors.lastname: Ni
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Xingxing
authors.initials: X
authors.lastname: He
authors.forename: Fuqiong
authors.initials: F
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Peihua
authors.initials: P
authors.lastname: Wang
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D004268:DNA-Binding Proteins; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000473:pathology*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D013312:Stress, Physiological; D014157:Transcription Factors; D014183:Transplantation, Heterologous; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C531408:mirn199 microRNA, human