Abstract
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.
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Acknowledgements
We thank Michael Worley and the Department of Scientific Publications at MD Anderson Cancer Center for editing the manuscript. This study was supported by a fellowship from the China Scholarship Council (201206380043 to SW), the National Natural Science Foundation of China (81071837, 81372410 and 30670627 to HY) and the Scientific and Technological Project of Guangdong, China (2008A030201009 and 2010B050700016 to HY) and by grants from the National Cancer Institute (R01-CA90853 to FXC), the Sister Institution Network Fund (FXC) and The University of Texas MD Anderson Functional Proteomics Core Facility (NCI Cancer Center Support Grant CA16672).
Author contributions
Conception and design: S Wang, Y Pan, H Yang, FX Claret. Development of methodology: S Wang, Y Pan, R Zhang, H Yang, FX Claret. Acquisition of data (provided animals, acquired and managed patients, provided facilities and so on): S Wang, Y Pan, R Zhang, T Xu, W Wu, C Wang, H Huang, H Yang, FX Claret. Analysis and interpretation of data (for example, statistical analysis, biostatistics, computational analysis): S Wang, FX Claret. Writing, review and/or revision of the manuscript: S Wang, Y Pan, FX Claret. Administrative, technical or material support (that is, reporting or organizing, data, constructing databases): H Yang, FX Claret. Study supervision: FX Claret. Other (helped with discussion and comments on the project): G Calin.
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Wang, S., Pan, Y., Zhang, R. et al. Hsa-miR-24-3p increases nasopharyngeal carcinoma radiosensitivity by targeting both the 3′UTR and 5′UTR of Jab1/CSN5. Oncogene 35, 6096–6108 (2016). https://doi.org/10.1038/onc.2016.147
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DOI: https://doi.org/10.1038/onc.2016.147
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