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

Molecular Cancer

Research

Pierre Busson¹  Samantha Wei-Man Lun²  Grace Tin-Yun Chung²  Chartia Ching-Mei Cheung²  Sharie Pui-Kei Siu²  Kin-Mang Lau²  Ka-Fai To³  Kwok-Wai Lo³  Sai-Wah Tsao⁴  Timothy Tak-Chun Yip⁵  Roger Kai-Cheong Ngan⁵  Xin-Yuan Guan⁶  Kwong-Wai Choy⁷ 

[1] CNRS-UMR 8126 and Institut de cancérologie Gustave Roussy, Université Paris-Sud-11, 39 rue Camille Desmoulins, F-94805, Villejuif, France;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;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;Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China;Department of Anatomy, University of Hong Kong, Hong Kong, People’s Republic of China;Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, People’s Republic of China;Department of Clinical Oncology, University of Hong Kong, Hong Kong, People’s Republic of China;Department of Obstetrics and Gynecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China;

关键词: Nasopharyngeal carcinoma;    MicroRNA;    miR-31;    FIH1;    MCM2;   

DOI  :  10.1186/1476-4598-13-184

 received in 2014-05-24, accepted in 2014-07-27,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundAs 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.MethodsThe 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.ResultsDownregulation 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 v itro 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.ConclusionsThe 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.

【 授权许可】

Unknown   
© Cheung et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.