Epstein–Barr virus BRLF1 induces genomic instability and progressive malignancy in nasopharyngeal carcinoma cells
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Sheng-Yen Huang1, Chung-Chun Wu1, Yu-Jhen Cheng1, Sheng-Ping Chou1, Yun-Jin Jiang2, Kuo-Chang Chu2, Ching-Hwa Tsai3, Su-Fang Lin1 and Jen-Yang Chen1,3
1National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan
2Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 35053, Taiwan
3Department of Microbiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
Jen-Yang Chen, email: [email protected]
Keywords: BRLF1, Epstein–Barr virus, nasopharyngeal carcinoma, chromosome mis-segregation, genomic instability
Received: March 31, 2017 Accepted: May 23, 2017 Published: September 05, 2017
Nasopharyngeal carcinoma (NPC) is a serious health problem in China and Southeast Asia. Relapse is the major cause of mortality, but mechanisms of relapse are mysterious. Epstein–Barr virus (EBV) reactivation and host genomic instability (GI) have correlated with NPC development. Previously, we reported that lytic early genes DNase and BALF3 induce genetic alterations and progressive malignancy in NPC cells, implying lytic proteins may be required for NPC relapse. In this study, we show that immediate early gene BRLF1 induces chromosome mis-segregation and genomic instability in the NPC cells. Similar phenomenon was also demonstrated in 293 and zebrafish embryonic cells. BRLF1 nuclear localization signal (NLS) mutant still induced genomic instability and inhibitor experiments revealed that BRLF1 interferes with chromosome segregation and induces genomic instability by activating Erk signaling. Furthermore, the chromosome aberrations and tumorigenic features of NPC cells were significantly increased with the rounds of BRLF1 expression, and these cells developed into larger tumor nodules in mice. Therefore, BRLF1 may be the important factor contributing to NPC relapse and targeting BRLF1 may benefit patients.
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