Hsa-miR-24-3p increases nasopharyngeal carcinoma radiosensitivity by targeting both the 3'UTR and 5'UTR of Jab1/CSN5

• Published in: Oncogene 2016-11, Vol.35 (47), p.6096-6108
• Main Authors: Wang, S, Pan, Y, Zhang, R, Xu, T, Wu, W, Wang, C, Huang, H, Calin, C A, Yang, H, Claret, F X
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; 5' Untranslated Regions; Analysis; Animals; Binding Sites; Carcinoma - genetics; Carcinoma - pathology; Carcinoma - radiotherapy; Care and treatment; Cell Line, Tumor; Cell Proliferation; Cellular signal transduction; COP9 Signalosome Complex; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Gene Silencing; Genetic aspects; Humans; Intracellular Signaling Peptides and Proteins - genetics; Mice; MicroRNA; MicroRNAs - genetics; Nasopharyngeal cancer; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - pathology; Nasopharyngeal Neoplasms - radiotherapy; Nucleic Acid Conformation; Peptide Hydrolases - genetics; Radiation Tolerance - genetics; Radiation, Ionizing; Radiotherapy; Recurrence; RNA Interference; Tumor Burden; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.147

Radiotherapy is the standard therapy for nasopharyngeal carcinoma (NPC); however, radioresistance can hinder successful treatment. Here we report that microRNA (miR)-24 acts as a tumor suppressor and radiosensitizer in NPC cells and xenografts by targeting Jab1/CSN5. Although accumulating evidence has shown that Jab1/CSN5 functions as an oncoprotein in human cancers, its regulation through miRs has not been described. In this study, we found that Jab1/CSN5 functioned in a manner opposite to that of miR-24 in NPC tumorigenesis and radioresistance. We demonstrated that miR-24 inhibits Jab1/CSN5 translation via direct binding to its 3' untranslated region (3'UTR) and 5'UTR, leading to tumor growth inhibition, and sensitizes NPC tumors to radiation in vivo. Furthermore, silencing Jab1/CSN5 phenocopied the function of miR-24 in NPC cells after ionizing radiation treatment, resulting in increased apoptosis. Finally, we analyzed 50 paired samples of primary and matched recurrent NPC tissues from 25 NPC patients and subjected them to high-throughput genomic quantitative nuclease protection assay for quantifying simultaneously miR and mRNA levels. Our results showed that miR-24 levels were significantly decreased in recurrent NPC and that levels of Jab1/CSN5, as its target, were higher than those in primary NPC. Together, our findings indicate that miR-24 inhibits NPC tumor growth and increases NPC radiosensitivity by directly regulating Jab1/CSN5 and that both miR-24 and Jab1/CSN5 can serve as prognostic markers for NPC recurrence; this, in turn, may provide a promising therapeutic strategy for reversing NPC radioresistance.