MicroRNA-19b-3p regulates nasopharyngeal carcinoma radiosensitivity by targeting TNFAIP3/NF-κB axis.

Teng Huang,Lu-Xi Qian,Jing Wu,Hong-Liang Yu,Ming-Yu Du,Nan Zhang,Jia-Jia Gu,Kai Ding,Jian-Zhong Wu,Li Yin,Zhi-Wei Lu,Xia He,Dan Chen

doi:10.1186/s13046-016-0465-1

Abstract

BackgroundNasopharyngeal carcinoma (NPC) is among the most common squamous cell carcinoma in South China and Southeast Asia. Radiotherapy is the primary treatment for NPC. However, radioresistance acts as a significant factor that limits the efficacy of radiotherapy for NPC patients. Growing evidence supports that microRNAs (miRNAs) play an important role in radiation response.MethodsReal-time quantitative PCR was used to analyze the expression of miR-19b-3p in NPC cell lines and NP69. miR-19b-3p expression profiles in NPC tissues were obtained from the Gene Expression Omnibus database. The effect of miR-19b-3p on radiosensitivity was evaluated by cell viability assays, colony formation assays and in vivo experiment. Apoptosis and cell cycle were examined by flow cytometry. Luciferase reporter assay was used to assess the target genes of miR-19b-3p. Expression of target proteins and downstream molecules were analyzed by Western blot.ResultsmiR-19b-3p was upregulated in NPC and served as an independent predictor for reduced patient survival. Radioresponse assays showed that miR-19b-3p overexpression resulted in decreased sensitivity to irradiation, whereas miR-19b-3p downregulation resulted in increased sensitivity to irradiation in vitro. Moreover, miR-19b-3p decreased the sensitivity of NPC cells to irradiation in vivo. Luciferase reporter assay confirmed that TNFAIP3 was a direct target gene of miR-19b-3p. Knockdown of TNFAIP3 reduced sensitivity to irradiation, whereas upregulation of TNFAIP3 expression reversed the inhibitory effects of miR-19b-3p on NPC cell radiosensitivity. Mechanistically, we found that miR-19b-3p increased NPC cell radioresistance by activating the TNFAIP3/ NF-κB axis.ConclusionsmiR-19b-3p contributes to the radioresistance of NPC by activating the TNFAIP3/ NF-κB axis. miR-19b-3p is a determinant of NPC radioresponse and may serve as a potential therapeutic target in NPC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0465-1) contains supplementary material, which is available to authorized users.

Highlights

Nasopharyngeal carcinoma (NPC) is among the most common squamous cell carcinoma in South China and Southeast Asia
Results miR-19b-3p is upregulated in NPC and associated with worse patient prognosis miR-19b-3p expression profile was obtained using the GEO database for human nasopharyngeal carcinoma samples
The mRNA level of miR-19b-3p in five NPC cell lines (CNE1, CNE2, 5-8F, 6-10B, and HNE1) and NP69 were investigated by quantitative RT-PCR (qRT-PCR) (Fig. 1b)

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is among the most common squamous cell carcinoma in South China and Southeast Asia. Radiotherapy is the primary treatment for NPC. Radioresistance acts as a significant factor that limits the efficacy of radiotherapy for NPC patients. Growing evidence supports that microRNAs (miRNAs) play an important role in radiation response. Nasopharyngeal carcinoma, which arises from the nasopharynx epithelium, is a common head and neck malignancy among the Southeast Asian populations. Radiotherapy is identified as the primary and only curative treatment for nasopharyngeal carcinoma [1]. Previous studies indicate that miRNAs directly affect radioresistance by interfering with specific pathways [4], including sensing DNA damage [5], repair of DNA double-strand breaks (DSBs) [6], cell cycle checkpoint. The mechanism underlying the role of miR-19b-3p in NPC radioresistance remains elusive

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