Abstract 1118: The role of Epstein-Barr virus-encoded miRNAs in ATM regulating DNA damage response in nasopharyngeal carcinoma

Abstract

Abstract Nasopharyngeal carcinoma (NPC) is an aggressive epithelial malignancy that has remarkably high incidence and mortality rates in Hong Kong and south China. It is well-known to be associated with Epstein-Barr virus (EBV) infection. Previous work in our team revealed that EBV-encoded miRNAs derived from the BARTs (miR-BARTs) were abundantly expressed in primary NPCs. They function in controlling apoptotic and immune responses in the infected cells during NPC development. Most recently, we attempted to use in silico method to predict cellular targets of miR-BARTs. Results suggested that there were multiple putative miR-BART binding sites on the 3’UTRs of an important DNA double-strand breaks (DSBs) repair gene, Ataxia-Telangiectasia-Mutant (ATM). The down-regulation of ATM mRNA and protein had also been demonstrated in our local primary NPC samples. Although the interaction of miR-BARTs on each suggested putative binding site had not been completely validated, our preliminary data indicated at least three EBV-encoded miRNAs (BART5-5p, BART9-3p and BART14-3p) were involved in repressing ATM expression in NPCs. They could work either alone or cooperatively to control ATM expression in transient assays. Notably, ectopic expression of these three miR-BARTs could successfully suppress γ irradiation-induced ATM activity in two EBV-negative cell lines, NP69 and HeLa. It had been reported that ATM null cells were defective to repair the DSB lesions and sensitive to the Poly(ADP-ribose) polymerase (PARP) inhibitor treatment in the presence of DNA-damaging agents. In contrast, the DSBs are effectively repaired in normal cells to retain genetic integrity. We believed that EBV infection, via miR-BARTs to reduce ATM activity and disrupt Homologous Recombination (HR) repair function, made the NPC cells sensitize to ionizing radiation and DNA-damaging agent treatment. Hence, the knowledge generated from this project is not only enhance our understanding of EBV biology, but also opens an avenue for the development of effective NPC therapies. Citation Format: RAYMOND Wai-Ming LUNG, Tom Pok-Man Hau, Wing-Po Chak, Joanna Hung-Man Tong, Ken Hung-On Yu, Sai-Wah Tsao, Kevin Yuk-Lap Yip, Ka-Fai To, Kwok-Wai Lo. The role of Epstein-Barr virus-encoded miRNAs in ATM regulating DNA damage response in nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1118.