EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma.
EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma.
复制标题
DOI：
10.1002/path.5018
复制
发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Lo KW
中科院分区：
文献类型：
--
作者：
Lung RW;Hau PM;Yu KH;Yip KY;Tong JH;Chak WP;Chan AW;Lam KH;Lo AK;Tin EK;Chau SL;Pang JC;Kwan JS;Busson P;Young LS;Yap LF;Tsao SW;To KF;Lo KW
鼻咽癌（NPC）是一种高度侵袭性的上皮恶性肿瘤，在中国南方和东南亚流行。它始终与潜伏性EB病毒（EBV）感染有关。在NPC中，miR-BARTs，即来源于BamH 1-A转录物的EBV编码的miRNAs，大量表达，并通过靶向各种细胞和病毒基因促进癌症发展。在这项研究中，我们通过小RNA测序建立了一组NPC患者来源的异种移植物和EBV阳性NPC细胞系中EBV编码的miRNA的全面转录谱。在40种miR-BART中，在这些肿瘤中始终检测到22种miRNAs的主要表达。在大量表达的EBV-miRNAs中，BART 5 - 5 p、BART 7 - 3 p、BART 9 - 3 p和BART 14 - 3 p可以通过与其3 '-UTR上的多个位点结合来负调控关键DNA双链断裂（DSB）修复基因共济失调毛细血管扩张突变（ATM）的表达。值得注意的是，这四种miR-BART的表达占肿瘤细胞中所有EBV编码的miRNA的10%以上，而ATM表达的下调通常在我们测试的所有测序样品中检测到。此外，在qRT-PCR（16例NP和45例NPC病例）和免疫组织化学染色（35例NP和46例NPC病例）分析中，也在原发性NPC组织中观察到ATM的下调。在瞬时转染试验中证明了BART 5 - 5 p、BART 7 - 3 p、BART 9 - 3 p和BART 14 - 3 p对ATM表达的调节。这些发现表明EBV使用miRNA机制作为控制NPC细胞中ATM信号通路的关键机制。通过抑制EBV阳性NPC细胞中的这些内源性miR-BARTs，我们进一步证明了miR-BARTs在抑制Zta诱导的裂解再活化中的新功能。这些发现意味着四种病毒miRNAs协同工作以调节ATM活性以响应DNA损伤并维持病毒潜伏期，从而促进NPC的肿瘤发生。© 2017作者。病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
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. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
登录
查看更多内容
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
7.3
作者：
Chung, Grace T. Y.;Lung, Raymond W. M.;Hui, Angela B. Y.;Yip, Kevin Y. L.;Woo, John K. S.;Chow, Chit;Tong, Carol Y. K.;Lee, Sau-Dan;Yuen, Jessie W. F.;Lun, Samantha W. M.;Tso, Ken K. Y.;Wong, Nathalie;Tsao, Sai-Wah;Yip, Timothy T. C.;Busson, Pierre;Kim, Hyungtae;Seo, Jeong-Sun;O'Sullivan, Brian;Liu, Fei-Fei;To, Ka-Fai;Lo, Kwok-Wai
通讯作者：
Lo, Kwok-Wai
影响因子：
14.5
作者：
Lee, SP
通讯作者：
Lee, SP
影响因子：
45.3
作者：
Fong, Peter C.;Yap, Timothy A.;Kaye, Stan B.
通讯作者：
Kaye, Stan B.
爱泼斯坦 - 巴尔病毒编码的microRNA mir-bart2下调病毒DNA聚合酶BALF5。
影响因子：
14.9
作者：
Barth, Stephanie;Pfuhl, Thorsten;Mamiani, Alfredo;Ehses, Claudia;Roemer, Klaus;Kremmer, Elisabeth;Jaeker, Christoph;Hoeck, Julia;Meister, Gunter;Graesser, Friedrich A.
通讯作者：
Graesser, Friedrich A.