title: Hsa-miR-24-3p increases nasopharyngeal carcinoma radiosensitivity by targeting both the 3'UTR and 5'UTR of Jab1/CSN5.
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.
authors.affiliation: Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People's Republic of China.|Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology, Affiliated Hospital, Wuxi Medical School, Jiangnan University, Wuxi, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Endoscopy, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Radiation Oncology, First People's Hospital of Foshan, Affiliated with Sun Yat-Sen University, Foshan, People's Republic of China.
authors.forename: T
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Radiation, Oncology, Cancer Center, Shantou Central Hospital, Shantou, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Calin
authors.affiliation: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Experimental Therapeutics Academic Program and Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: F X
authors.initials: FX
authors.lastname: Claret
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000818:Animals; D001665:Binding Sites; D000075686:COP9 Signalosome Complex; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D009690:Nucleic Acid Conformation; D010447:Peptide Hydrolases / Q000235:genetics*; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing; D012008:Recurrence; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D047908:Intracellular Signaling Peptides and Proteins; C543845:MIRN24 microRNA, human; D035683:MicroRNAs; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex