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

Lung, R. W. M. and Hau, P. M. and Yu, K. H. O. and Yip, K. Y. and Tong, J. H. M. and Chak, W. P. and Chan, A. W. H. and Lam, K. H. and Lo, A. K. F. and Tin, E. K. Y. and Chau, S. L. and Pang, J. C. S. and Kwan, J. S. H. and Busson, P. and Young, L. S. and Yap, L. F. and Tsao, S. W. and To, K. F. and Lo, K. W. (2018) EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma. Journal of Pathology, 244 (4). pp. 394-407. ISSN 0022-3417, DOI https://doi.org/10.1002/path.5018.

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Abstract

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. (c) 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Item Type:	Article
Funders:	UNSPECIFIED
Subjects:	R Medicine > RK Dentistry > Practice of dentistry. Dental economics
Divisions:	Faculty of Dentistry > Dept of Oral Biology
Depositing User:	Mr Ahmad Azwan Azman
Date Deposited:	23 Feb 2022 00:29
Last Modified:	23 Feb 2022 00:29
URI:	http://eprints.um.edu.my/id/eprint/18912

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