title: miR-31 is consistently inactivated in EBV-associated nasopharyngeal carcinoma and contributes to its tumorigenesis.
abstract: BACKGROUND
  As a distinctive type of head and neck cancers, nasopharyngeal carcinoma (NPC) is genesis from the clonal Epstein-Barr virus (EBV)-infected nasopharyngeal epithelial cells accumulated with multiple genetic lesions. Among the recurrent genetic alterations defined, loss of 9p21.3 is the most frequent early event in the tumorigenesis of EBV-associated NPC. In addition to the reported CDKN2A/p16, herein, we elucidated the role of a miRNA, miR-31 within this 9p21.3 region as NPC-associated tumor suppressor.
  
  
  METHODS
  The expression and promoter methylation of miR-31 were assessed in a panel of NPC tumor lines and primary tumors. Its in vitro and in vivo tumor suppression function was investigated through the ectopic expression of miR-31 in NPC cells. We also determined the miR-31 targeted genes and its involvement in the growth in NPC.
  
  
  RESULTS
  Downregulation of miR-31 expression was detected in almost all NPC cell line, patient-derived xenografts (PDXs) and primary tumors. Both homozygous deletion and promoter hypermethylation were shown to be major mechanisms for miR-31 silencing in this cancer. Strikingly, loss of miR-31 was also obviously observed in the dysplastic lesions of nasopharynx. Restoration of miR-31 in C666-1 cells inhibited the cell proliferation, colony-forming and migratory capacities. Dramatic reduction of in vitro anchorage-independent growth and in vivo tumorigenic potential were demonstrated in the stable clones expressing miR-31. Furthermore, we proved that miR-31 suppressed the NPC cell growth via targeting FIH1 and MCM2.
  
  
  CONCLUSIONS
  The findings provide strong evidence to support miR-31 as a new NPC-associated tumor suppressor on 9p21.3 region. The inactivation of miR-31 may contribute to the early development of NPC.
authors.forename: Chartia Ching-Mei
authors.initials: CC
authors.lastname: Cheung
authors.forename: Grace Tin-Yun
authors.initials: GT
authors.lastname: Chung
authors.forename: Samantha Wei-Man
authors.initials: SW
authors.lastname: Lun
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.forename: Kwong-Wai
authors.initials: KW
authors.lastname: Choy
authors.forename: Kin-Mang
authors.initials: KM
authors.lastname: Lau
authors.forename: Sharie Pui-Kei
authors.initials: SP
authors.lastname: Siu
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.forename: Roger Kai-Cheong
authors.initials: RK
authors.lastname: Ngan
authors.forename: Timothy Tak-Chun
authors.initials: TT
authors.lastname: Yip
authors.forename: Pierre
authors.initials: P
authors.lastname: Busson
authors.forename: Sai-Wah
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, People's Republic of China. kwlo@cuhk.edu.hk.
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D002277:Carcinoma; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006720:Homozygote; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D064111:Minichromosome Maintenance Complex Component 2 / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2
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