Journal
ONCOTARGET
Volume 8, Issue 45, Pages 78948-78964Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20695
Keywords
BRLF1; Epstein-Barr virus; nasopharyngeal carcinoma; chromosome mis-segregation; genomic instability
Categories
Funding
- National Health Research Institutes
- National Science Council
- Ministry of Science and Technology, Taiwan [NSC102-2325-B-400-021, NSC103-2325-B-400-008, MOST 104-2320-B-400-016, MOST 105-2325-B-400-016, MOST 106-2320-B-400-015]
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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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