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

• Published in: Molecular cancer Vol. 13; no. 1; p. 184
• Main Authors: Cheung, Chartia Ching-Mei, Chung, Grace Tin-Yun, Lun, Samantha Wei-Man, To, Ka-Fai, Choy, Kwong-Wai, Lau, Kin-Mang, Siu, Sharie Pui-Kei, Guan, Xin-Yuan, Ngan, Roger Kai-Cheong, Yip, Timothy Tak-Chun, Busson, Pierre, Tsao, Sai-Wah, Lo, Kwok-Wai
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 07.08.2014; BioMed Central
• Subjects: Analysis; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinoma; Cell growth; Cell Movement - genetics; Cell Proliferation; Cell Survival - genetics; Chromosomes; Colleges & universities; Comparative Genomic Hybridization; DNA Methylation - genetics; Down-Regulation - genetics; Epstein-Barr virus; Experiments; Gene Deletion; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Herpesvirus 4, Human - physiology; Homozygote; Humans; Hybridization; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Minichromosome Maintenance Complex Component 2 - metabolism; Mixed Function Oxygenases - metabolism; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - pathology; Nasopharyngeal Neoplasms - virology; Oncology; Phosphorylation; Physiological aspects; Promoter Regions, Genetic; Repressor Proteins - metabolism; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors; Hong Kong; China
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-13-184

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. 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. 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. 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.