miR-31 is consistently inactivated in EBV-associated nasopharyngeal carcinoma and contributes to its tumorigenesis

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• 作者：Chartia Ching-Mei Cheung (1)
  Grace Tin-Yun Chung (1)
  Samantha Wei-Man Lun (1)
  Ka-Fai To (1) (2)
  Kwong-Wai Choy (3)
  Kin-Mang Lau (1)
  Sharie Pui-Kei Siu (1)
  Xin-Yuan Guan (4)
  Roger Kai-Cheong Ngan (5)
  Timothy Tak-Chun Yip (5)
  Pierre Busson (6)
  Sai-Wah Tsao (7)
  Kwok-Wai Lo (1) (2)
  
  1. 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鈥檚 Republic of China
  2. Li Ka Shing Institute of Health Science ; The Chinese University of Hong Kong ; Hong Kong ; People鈥檚 Republic of China
  3. Department of Obstetrics and Gynecology ; Prince of Wales Hospital ; The Chinese University of Hong Kong ; Hong Kong ; People鈥檚 Republic of China
  4. Department of Clinical Oncology ; University of Hong Kong ; Hong Kong ; People鈥檚 Republic of China
  5. Department of Clinical Oncology ; Queen Elizabeth Hospital ; Hong Kong ; People鈥檚 Republic of China
  6. CNRS-UMR 8126 and Institut de canc茅rologie Gustave Roussy ; Universit茅 Paris-Sud-11 ; 39 rue Camille Desmoulins ; F-94805 ; Villejuif ; France
  7. Department of Anatomy ; University of Hong Kong ; Hong Kong ; People鈥檚 Republic of China
  
• 关键词：Nasopharyngeal carcinoma ; MicroRNA ; miR ; 31 ; FIH1 ; MCM2
• 刊名：Molecular Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：13
• 期：1
• 全文大小：5,123 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

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.