Abstract
Resistance to radiotherapy is one of the main causes of treatment failure in patients with nasopharyngeal carcinoma (NPC). Epstein-Barr virus (EBV) infection is an important factor in the pathogenesis of NPC, and EBV-encoded microRNAs (miRNAs) promote NPC progression. However, the role of EBV-encoded miRNAs in the radiosensitivity of NPC remains unclear. Here, we investigated the effects of EBV-miR-BART8-3p on radiotherapy resistance in NPC cells in vitro and in vivo, and explored the underlying molecular mechanisms. Inhibitors of ataxia telangiectasia mutated (ATM)/ataxia telangiectasia mutated and Rad3-related (ATR) (KU60019 and AZD6738, respectively) were used to examine radiotherapy resistance. We proved that EBV-miR-BART8-3p promoted NPC cell proliferation in response to irradiation in vitro and associated with the induction of cell cycle arrest at the G2/M phase, which was a positive factor for the DNA repair after radiation treatment. Besides, EBV-miR-BART8-3p could increase the size of xenograft tumors significantly in nude mice. Treatment with KU60019 or AZD6738 increased the radiosensitivity of NPC by suppressing the expression of p-ATM and p-ATR. The present results indicate that EBV-miR-BART8-3p promotes radioresistance in NPC by modulating the activity of ATM/ATR signaling pathway.
Highlights
Nasopharyngeal carcinoma (NPC) is a common malignant tumor in Southern China, a high incidence is reported in Southeast Asia, North Africa, Alaska and the Mediterranean basin [1]
The results of the Cell Counting Kit-8 (CCK-8) assay indicated that Epstein-Barr virus (EBV)-miR-BART8-3p increased proliferation of NPC cells compared with the negative control (NC) cells (Figure 1A)
Flow cytometry analysis showed that the rate of apoptosis in cells overexpressing EBV-miR-BART8-3p was lower than that in NC cells (Figure 1B); this was confirmed by quantitative analysis (Figure 1C)
Summary
Nasopharyngeal carcinoma (NPC) is a common malignant tumor in Southern China, a high incidence is reported in Southeast Asia, North Africa, Alaska and the Mediterranean basin [1]. The local control rate and 5-year overall survival of patients with NPC exceed 90 and 80%, respectively3]. Technological advances have improved the prognosis of NPC, radioresistance remains the main cause of therapy failure and distant metastasis [4]. A better understanding of the mechanism underlying radioresistance of NPC may improve survival and facilitate design of therapeutic strategies. Several factors are involved in the etiology of NPC; among these, Epstein-Barr virus (EBV) infection plays a central role [5]. EBV is the first human virus shown to encode miRNAs; 25 EBV-miRNA precursors containing 48 mature miRNAs have been identified within two regions of the EBV genome [6,7]. EBV-encoded miRNAs promote migration and proliferation and inhibit apoptosis of NPC
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