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Wei Huang,1,2 Jie Liu,3 Shanbiao Hu,4 Guangqing Shi,1 Zhong Yong,1 Jian Li,1 Juan Qiu,1 Yan Cao,1 Li Yuan1 1Department of Nuclear Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3Department of Pathology, Changsha Central Hospital, Changsha, Hunan, People’s Republic of China; 4Department of Urological Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Li YuanDepartment of Nuclear Medicine, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, People’s Republic of ChinaEmail li_yuan2019@126.comBackground: Radioresistance is the leading cause of treatment failure for nasopharyngeal carcinoma (NPC). Therefore, screening the critical regulators in radioresistance and revealing the underlying mechanisms is imperative for improvement of therapeutical efficacy in NPC.Materials and methods: Our previous study has proved that miR-181a may serve as a pro-radioresistant miRNA. In this study, we explored the expression of miR-181a in NPC, especially in radioresistant NPC samples, by qPCR. Moreover, the clinical significance of miR-181a level was also analyzed. Furthermore, the functions of miR-181a, both in vitro and in vivo, were detected via a serial of assays such as CCK-8, plate clone survival, apoptosis, and xenograft tumor model. The downstream target of miR-181a was also validated by dual luciferase reporter assay and the roles of miR-181a’s target in the regulation of NPC radioresistance were investigated.Results: The results revealed that miR-181a was significantly upregulated in NPC, especially in radioresistant NPC. MiR-181a level is positively correlated to lymph node metastasis and advanced TNM stages and negatively associated with overall survival rate in NPC. Ectopic expression of miR-181a in radiosensitive NPC cells, or overexpression of miR-181a inhibitor in radioresistant NPC cells, could enhance or impair the radioresistance of NPC cells supported by the results from both in vitro and in vivo, respectively. Mechanistically, dual luciferase report assay indicated that miR-181a could directly target RKIP. Moreover, both in vitro and in vivo experimental outcomes indicated that RKIP restoration and knockdown could antagonize the effects of miR-181a and miR-181a inhibitor in the regulation of NPC radioresistance.Conclusion: Collectively, the findings of this study proved that miR-181a is upregulated and promotes radioresistance by targeting RKIP in NPC. Targeting miR-181a/RKIP axis may be a valid path for reinforcing radiosensitivity and eventually improving the outcomes of clinical treatment in NPC.Keywords: nasopharyngeal carcinoma, radioresistance, miR-181a, RKIP |
