EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma

Lung, Raymond W.M. and Hau, Pok Man and Yu, Ken H.O. and Yip, Kevin Y. and Tong, Joanna H.M. and Chak, Wing Po and Chan, Anthony W.H. and Lam, Ka Hei and Lo, Angela Kwok Fung and Tin, Edith K.Y. and Chau, Shuk Ling and Pang, Jesse C.S. and Kwan, Johnny S.H. and Busson, Pierre and Young, Lawrence S. and Yap, Lee Fah and Tsao, Sai Wah and To, Ka Fai and Lo, Kwok Wai (2018) EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma. The Journal of Pathology, 244 (4). pp. 394-407. ISSN 0022-3417, DOI https://doi.org/10.1002/path.5018.

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Official URL: https://doi.org/10.1002/path.5018


Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein–Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing. Among the 40 miR-BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV-miRNAs, BART5-5p, BART7-3p, BART9-3p, and BART14-3p could negatively regulate the expression of a key DNA double-strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'-UTR. Notably, the expression of these four miR-BARTs represented more than 10% of all EBV-encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT-PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5-5p, BART7-3p, BART9-3p, and BART14-3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR-BARTs in EBV-positive NPC cells, we further demonstrated the novel function of miR-BARTs in inhibiting Zta-induced lytic reactivation. These findings imply that the four viral miRNAs work co-operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC.

Item Type: Article
Funders: Focus Investigation Scheme-A and VC’s One-off Discretionary Fund (VCF2014017) from the Chinese University of Hong Kong, Research Grants Council of Hong Kong-GRF (471211, 470312, 471413, 14104415 and 14138016), Collaborative Research Fund (CUHK8/CRF/11R and C7027-16G), Theme-Based Research Scheme (T12-401/13R), Fundamental Research Grant Scheme (FP013-2016) from the Ministry of Higher Education Malaysia, Newton-Ungku Omar Fund (IF016-2017; MR/P013201/1) from the Academy of Sciences Malaysia, Medical Research Council UK
Uncontrolled Keywords: ATM serine/threonine kinase (ATM); EBV-miRNAs; Epstein–Barr virus; nasopharyngeal carcinoma; transcriptome sequencing
Subjects: R Medicine
Divisions: Faculty of Dentistry
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 29 May 2019 03:18
Last Modified: 23 Dec 2019 04:32
URI: http://eprints.um.edu.my/id/eprint/21381

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