{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T11:10:18Z","timestamp":1784373018732,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2018,4,17]],"date-time":"2018-04-17T00:00:00Z","timestamp":1523923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma derived from the epithelium of the post-nasal cavity, with a unique geographic and ethnic distribution. Epstein\u2013Barr virus (EBV) is an etiological agent of NPC, but how it contributes to carcinogenesis is not completely clear. Although it is thought that EBV latency participates in the development of NPC, increasing evidence reveals that the lytic cycle also plays an important role in the carcinogenic process. In this review, we summarize our recent studies on how EBV reactivation causes genomic instability and accelerates tumorigenesis in epithelial cells. The roles of three lytic genes, namely, BRLF1, BGLF5 and BALF3, in this process are also introduced. Moreover, blocking EBV reactivation using natural compounds may help delay the progression of NPC tumorigenesis. These studies provide a new insight into NPC carcinogenesis and raise the possibility that inhibition of EBV reactivation may be a novel approach to prevent the relapse of NPC.<\/jats:p>","DOI":"10.3390\/cancers10040120","type":"journal-article","created":{"date-parts":[[2018,4,18]],"date-time":"2018-04-18T03:51:13Z","timestamp":1524023473000},"page":"120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Perspective: Contribution of Epstein\u2013Barr virus (EBV) Reactivation to the Carcinogenicity of Nasopharyngeal Cancer Cells"],"prefix":"10.3390","volume":"10","author":[{"given":"Chung-Chun","family":"Wu","sequence":"first","affiliation":[{"name":"National Institute of Cancer Research, National Health Research Institutes, Zhunan 350, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Yeu","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Yen","family":"Huang","sequence":"additional","affiliation":[{"name":"National Institute of Cancer Research, National Health Research Institutes, Zhunan 350, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Hsin","family":"Chiu","sequence":"additional","affiliation":[{"name":"National Institute of Cancer Research, National Health Research Institutes, Zhunan 350, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Huei","family":"Lee","sequence":"additional","affiliation":[{"name":"National Institute of Cancer Research, National Health Research Institutes, Zhunan 350, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen-Yang","family":"Chen","sequence":"additional","affiliation":[{"name":"National Institute of Cancer Research, National Health Research Institutes, Zhunan 350, Taiwan"},{"name":"Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1093\/oxfordjournals.epirev.a036130","article-title":"Etiology of nasopharyngeal carcinoma: A review","volume":"15","author":"Hildesheim","year":"1993","journal-title":"Epidemiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1046\/j.1365-2273.2001.00449.x","article-title":"The aetiology of nasopharyngeal carcinoma","volume":"26","author":"McDermott","year":"2001","journal-title":"Clin. Otolaryngol. Allied Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1056\/NEJMoa011610","article-title":"Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men","volume":"345","author":"Chien","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Cao, S.M., Liu, Z., Jia, W.H., Huang, Q.H., Liu, Q., Guo, X., and Hong, M.H. (2011). Fluctuations of Epstein-Barr virus serological antibodies and risk for nasopharyngeal carcinoma: A prospective screening study with a 20-year follow-up. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019100"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/sj.bjc.6603609","article-title":"Sustained elevation of Epstein-Barr virus antibody levels preceding clinical onset of nasopharyngeal carcinoma","volume":"96","author":"Ji","year":"2007","journal-title":"Br. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/nrc1452","article-title":"Epstein-Barr virus: 40 years on","volume":"4","author":"Young","year":"2004","journal-title":"Nat. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.tim.2016.03.008","article-title":"Viral carcinogenesis beyond malignant transformation: EBV in the progression of human cancers","volume":"24","author":"Pagano","year":"2016","journal-title":"Trends Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41698-017-0018-x","article-title":"EBV based cancer prevention and therapy in nasopharyngeal carcinoma","volume":"1","author":"Cao","year":"2017","journal-title":"Precis. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13993","DOI":"10.1128\/JVI.79.22.13993-14003.2005","article-title":"Epstein-Barr virus lytic infection contributes to lymphoproliferative disease in a SCID mouse model","volume":"79","author":"Hong","year":"2005","journal-title":"J. Virol."},{"key":"ref_10","first-page":"1711","article-title":"The Epstein-Barr virus encoded cytokine viral interleukin-10 enhances transformation of human B lymphocytes","volume":"11","author":"Stuart","year":"1995","journal-title":"Oncogene"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.canlet.2005.06.023","article-title":"Anti-apoptotic role of BARF1 in gastric cancer cells","volume":"238","author":"Wang","year":"2006","journal-title":"Cancer Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.7150\/ijbs.16564","article-title":"Epstein-Barr virus lytic reactivation regulation and its pathogenic role in carcinogenesis","volume":"12","author":"Li","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1002\/ijc.2910200504","article-title":"Nasopharyngeal carcinoma: Significance of changes in Epstein-Barr virus-related antibody patterns following therapy","volume":"20","author":"Henle","year":"1977","journal-title":"Int. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/em.2850180414","article-title":"Micronuclei as an index of cytogenetic damage: Past, present, and future","volume":"18","author":"Heddle","year":"1991","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8857","DOI":"10.1128\/JVI.73.10.8857-8866.1999","article-title":"Requirement for cell-to-cell contact in Epstein-Barr virus infection of nasopharyngeal carcinoma cells and keratinocytes","volume":"73","author":"Chang","year":"1999","journal-title":"J. Virol."},{"key":"ref_17","first-page":"713","article-title":"Establishment and characterization of two nasopharyngeal carcinoma cell lines","volume":"62","author":"Lin","year":"1990","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1002\/ijc.24179","article-title":"Recurrent chemical reactivations of EBV promotes genome instability and enhances tumor progression of nasopharyngeal carcinoma cells","volume":"124","author":"Fang","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_19","unstructured":"Rickinson, A.B., and Kieff, E. (2001). Epstein-Barr Virus, Lippincott Williams & Wilkins. [4th ed.]."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1093\/nar\/gkp1169","article-title":"Epstein-Barr virus DNase (BGLF5) induces genomic instability in human epithelial cells","volume":"38","author":"Wu","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4962","DOI":"10.1128\/JVI.00063-14","article-title":"Epstein-Barr virus BALF3 has nuclease activity and mediates mature virion production during the lytic cycle","volume":"88","author":"Chiu","year":"2014","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8583","DOI":"10.18632\/oncotarget.2323","article-title":"Epstein-Barr virus BALF3 mediates genomic instability and progressive malignancy in nasopharyngeal carcinoma","volume":"5","author":"Chiu","year":"2014","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"78948","DOI":"10.18632\/oncotarget.20695","article-title":"Epstein-Barr virus BRLF1 induces genomic instability and progressive malignancy in nasopharyngeal carcinoma cells","volume":"8","author":"Huang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0304-3835(95)03786-V","article-title":"Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC","volume":"93","author":"Mirvish","year":"1995","journal-title":"Cancer Lett."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Huang, S.Y., Fang, C.Y., Wu, C.C., Tsai, C.H., Lin, S.F., and Chen, J.Y. (2013). Reactive oxygen species mediate Epstein-Barr virus reactivation by N-methyl-N\u2032-nitro-N-nitrosoguanidine. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0084919"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.cbi.2010.09.020","article-title":"N-methyl-N\u2032-nitro-N-nitrosoguanidine induces and cooperates with 12-O-tetradecanoylphorbol-1,3-acetate\/sodium butyrate to enhance Epstein-Barr virus reactivation and genome instability in nasopharyngeal carcinoma cells","volume":"188","author":"Huang","year":"2010","journal-title":"Chem. Biol. Interact."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Fang, C.Y., Huang, S.Y., Wu, C.C., Hsu, H.Y., Chou, S.P., Tsai, C.H., and Chen, J.Y. (2012). The synergistic effect of chemical carcinogens enhances Epstein-Barr virus reactivation and tumor progression of nasopharyngeal carcinoma cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044810"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1002\/mc.21926","article-title":"Inhibition of Epstein-Barr virus reactivation in nasopharyngeal carcinoma cells by dietary sulforaphane","volume":"52","author":"Wu","year":"2013","journal-title":"Mol. Carcinog."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.antiviral.2016.05.007","article-title":"Luteolin inhibits Epstein-Barr virus lytic reactivation by repressing the promoter activities of immediate-early genes","volume":"132","author":"Wu","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12929-016-0313-9","article-title":"Inhibition of Epstein-Barr virus reactivation by the flavonoid apigenin","volume":"24","author":"Wu","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18999","DOI":"10.18632\/oncotarget.7967","article-title":"EBV reactivation as a target of luteolin to repress NPC tumorigenesis","volume":"7","author":"Wu","year":"2016","journal-title":"Oncotarget"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/10\/4\/120\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:00:59Z","timestamp":1760194859000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/10\/4\/120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,17]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,4]]}},"alternative-id":["cancers10040120"],"URL":"https:\/\/doi.org\/10.3390\/cancers10040120","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,17]]}}}