Mechanism of Epstein-Barr virus latent infection-related genes in tumors caused by them_West China Medical Journal

Authors：

WANG Zhonghao , ZHANG Keyi , FENG Shu ,  TAO Chuanmin

Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

TAO Chuanmin, Email: taocm@scu.edu.cn

Keywords：

Lymphoma; Nasopharyngeal carcinoma; Epstein-Barr nuclear antigen; Latent membrane protein

DOI：

10.7507/1002-0179.202007037

Video：

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Epstein-Barr (EB) virus infection is associated with various tumors of lymphoid and epithelial origin. EB virus exists in most humans as a latent infection. EB virus latent infection-related genes play a key role in the EB virus latent infection, and also play an important role in promoting the occurrence and development of related tumors. This article will briefly introduce the characteristics of EB virus latent infection, the protein coding genes and non-coding genes related to EB virus latent infection (including EB virus nuclear antigen genes, EB virus latent membrane protein genes, EB virus encoded small RNA genes and EB virus microRNA genes), and the main functional mechanism of these EB virus latent infection-related genes in EB virus latent infection and subsequent tumorigenesis. The purpose is to providea theoretical basis for a comprehensive understanding of the EB virus latent infection and the mechanism of tumors caused by EB virus.

Citation： WANG Zhonghao, ZHANG Keyi, FENG Shu, TAO Chuanmin. Mechanism of Epstein-Barr virus latent infection-related genes in tumors caused by them. West China Medical Journal, 2021, 36(8): 1108-1114. doi: 10.7507/1002-0179.202007037 Copy

1.	Shannon-Lowe C, Rickinson A. The global landscape of EBV-associated tumors. Front Oncol, 2019, 9: 713.
2.	Khan G, Hashim MJ. Global burden of deaths from Epstein-Barr virus attributable malignancies 1990-2010. Infect Agent Cancer, 2014, 9(1): 38.
3.	Odumade OA, Hogquist KA, Balfour HH Jr. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev, 2011, 24(1): 193-209.
4.	Yu J, Liang Q, Wang J, et al. REC8 functions as a tumor suppressor and is epigenetically downregulated in gastric cancer, especially in EBV-positive subtype. Oncogene, 2017, 36(2): 182-193.
5.	Dheekollu J, Wiedmer A, Sentana-Lledo D, et al. HCF1 and OCT2 cooperate with EBNA1 to enhance oriP-dependent transcription and episome maintenance of latent Epstein-Barr virus. J Virol, 2016, 90(11): 5353-5367.
6.	De Leo A, Calderon A, Lieberman PM. Control of viral latency by episome maintenance proteins. Trends Microbiol, 2020, 28(2): 150-162.
7.	Jiang L, Xie C, Lung HL, et al. EBNA1-targeted inhibitors: novel approaches for the treatment of Epstein-Barr virus-associated cancers. Theranostics, 2018, 8(19): 5307-5319.
8.	Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer, 2004, 4(10): 757-768.
9.	Humme S, Reisbach G, Feederle R, et al. The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold. Proc Natl Acad Sci USA, 2003, 100(19): 10989-10994.
10.	Wang L, Tian WD, Xu X, et al. Epstein-Barr virus nuclear antigen 1 (EBNA1) protein induction of epithelial-mesenchymal transition in nasopharyngeal carcinoma cells. Cancer, 2014, 120(3): 363-372.
11.	Messick TE, Smith GR, Soldan SS, et al. Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth. Sci Transl Med, 2019, 11(482): eaau5612.
12.	Henkel T, Ling PD, Hayward SD, et al. Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. Science, 1994, 265(5168): 92-95.
13.	Ling PD, Rawlins DR, Hayward SD. The Epstein-Barr virus immortalizing protein EBNA-2 is targeted to DNA by a cellular enhancer-binding protein. Proc Natl Acad Sci USA, 1993, 90(20): 9237-9241.
14.	Lu F, Chen HS, Kossenkov AV, et al. EBNA2 drives formation of new chromosome binding sites and target genes for B-cell master regulatory transcription factors RBP-jκ and EBF1. PLoS Pathog, 2016, 12(1): e1005339.
15.	Rabson M, Gradoville L, Heston L, et al. Non-immortalizing P3J-HR-1 Epstein-Barr virus: a deletion mutant of its transforming parent, Jijoye. J Virol, 1982, 44(3): 834-844.
16.	Lu F, Wiedmer A, Martin KA, et al. Coordinate regulation of TET2 and EBNA2 controls the DNA methylation state of latent Epstein-Barr virus. J Virol, 2017, 91(20): e00804-17.
17.	Anastasiadou E, Stroopinsky D, Alimperti S, et al. Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas. Leukemia, 2019, 33(1): 132-147.
18.	Bhattacharjee S, Ghosh Roy S, Bose P, et al. Role of EBNA-3 family proteins in EBV associated B-cell Lymphomagenesis. Front Microbiol, 2016, 7: 457.
19.	Maruo S, Zhao B, Johannsen E, et al. Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. Proc Natl Acad Sci USA, 2011, 108(5): 1919-1924.
20.	Pei Y, Singh RK, Shukla SK, et al. Epstein-Barr virus nuclear antigen 3C facilitates cell proliferation by regulating cyclin D2. J Virol, 2018, 92(18): e00663-18.
21.	Bazot Q, Deschamps T, Tafforeau L, et al. Epstein-Barr virus nuclear antigen 3A protein regulates CDKN2B transcription via interaction with MIZ-1. Nucleic Acids Res, 2014, 42(15): 9700-9716.
22.	Styles CT, Paschos K, White RE, et al. The cooperative functions of the EBNA3 proteins are central to EBV persistence and latency. Pathogens, 2018, 7(1): 31.
23.	Shukla SK, Jha HC, El-Naccache DW, et al. An EBV recombinant deleted for residues 130-159 in EBNA3C can deregulate p53/Mdm2 and Cyclin D1/CDK6 which results in apoptosis and reduced cell proliferation. Oncotarget, 2016, 7(14): 18116-18134.
24.	Zhang S, Pei Y, Lang F, et al. EBNA3C facilitates RASSF1A downregulation through ubiquitin-mediated degradation and promoter hypermethylation to drive B-cell proliferation. PLoS Pathog, 2019, 15(1): e1007514.
25.	Bhattacharjee S, Bose P, Patel K, et al. Transcriptional and epigenetic modulation of autophagy promotes EBV oncoprotein EBNA3C induced B-cell survival. Cell Death Dis, 2018, 9(6): 605.
26.	Gunnell A, Webb HM, Wood CD, et al. RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth. Nucleic Acids Res, 2016, 44(10): 4636-4650.
27.	White RE, Rämer PC, Naresh KN, et al. EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors. J Clin Invest, 2012, 122(4): 1487-1502.
28.	Paschos K, Bazot Q, Ho G, et al. Core binding factor (CBF) is required for Epstein-Barr virus EBNA3 proteins to regulate target gene expression. Nucleic Acids Res, 2017, 45(5): 2368-2383.
29.	Kang MS, Kieff E. Epstein-Barr virus latent genes. Exp Mol Med, 2015, 47(1): e131.
30.	Nakada R, Matsuura Y. Crystal structure of importin-α bound to the nuclear localization signal of Epstein-Barr virus EBNA-LP protein. Protein Sci, 2017, 26(6): 1231-1235.
31.	Szymula A, Palermo RD, Bayoumy A, et al. Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naïve B cells, and facilitates recruitment of transcription factors to the viral genome. PLoS Pathog, 2018, 14(2): e1006890.
32.	Devergne O, Hatzivassiliou E, Izumi KM, et al. Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activation. Mol Cell Biol, 1996, 16(12): 7098-7108.
33.	Luftig M, Prinarakis E, Yasui T, et al. Epstein-Barr virus latent membrane protein 1 activation of NF-kappaB through IRAK1 and TRAF6. Proc Natl Acad Sci USA, 2003, 100(26): 15595-15600.
34.	Jiang Y, Yan B, Lai W, et al. Repression of Hox genes by LMP1 in nasopharyngeal carcinoma and modulation of glycolytic pathway genes by HoxC8. Oncogene, 2015, 34(50): 6079-6091.
35.	Xiao L, Hu ZY, Dong X, et al. Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy. Oncogene, 2014, 33(37): 4568-4578.
36.	Aga M, Bentz GL, Raffa S, et al. Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene, 2014, 33(37): 4613-4622.
37.	Meckes DG Jr, Gunawardena HP, Dekroon RM, et al. Modulation of B-cell exosome proteins by gamma herpesvirus infection. Proc Natl Acad Sci USA, 2013, 110(31): E2925-E2933.
38.	Hurwitz SN, Nkosi D, Conlon MM, et al. CD63 regulates Epstein-Barr virus LMP1 exosomal packaging, enhancement of vesicle production, and noncanonical NF-κB signaling. J Virol, 2017, 91(5): e02251-16.
39.	Incrocci R, McAloon J, Montesano M, et al. Epstein-Barr virus LMP2A utilizes Syk and PI3K to activate NF-κB in B-cell lymphomas to increase MIP-1α production. J Med Virol, 2019, 91(5): 845-855.
40.	Rancan C, Schirrmann L, Hüls C, et al. Latent membrane protein LMP2A impairs recognition of EBV-infected cells by CD8⁺ T Cells. PLoS Pathog, 2015, 11(6): e1004906.
41.	Minamitani T, Ma Y, Zhou H, et al. Mouse model of Epstein-Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease. Proc Natl Acad Sci USA, 2017, 114(18): 4751-4756.
42.	Ma SD, Tsai MH, Romero-Masters JC, et al. Latent membrane protein 1 (LMP1) and LMP2A collaborate to promote Epstein-Barr virus-induced B cell lymphomas in a cord blood-humanized mouse model but are not essential. J Virol, 2017, 91(7): e01928-16.
43.	Zhu J, Kamara S, Cen D, et al. Generation of novel affibody molecules targeting the EBV LMP2A N-terminal domain with inhibiting effects on the proliferation of nasopharyngeal carcinoma cells. Cell Death Dis, 2020, 11(4): 213.
44.	Ahmed M, Lopez-Albaitero A, Pankov D, et al. TCR-mimic bispecific antibodies targeting LMP2A show potent activity against EBV malignancies. JCI Insight, 2018, 3(4): e97805.
45.	Rechsteiner MP, Berger C, Zauner L, et al. Latent membrane protein 2B regulates susceptibility to induction of lytic Epstein-Barr virus infection. J Virol, 2008, 82(4): 1739-1747.
46.	Moss WN, Lee N, Pimienta G, et al. RNA families in Epstein-Barr virus. RNA Biol, 2014, 11(1): 10-17.
47.	Moss WN, Steitz JA. Genome-wide analyses of Epstein-Barr virus reveal conserved RNA structures and a novel stable intronic sequence RNA. BMC Genomics, 2013, 14: 543.
48.	Zerbe CM, Cole JL. Regulation of protein kinase R by Epstein-Barr virus EBER1 RNA. Biochemistry, 2020, 59(12): 1252-1260.
49.	Lee N, Yario TA, Gao JS, et al. EBV noncoding RNA EBER2 interacts with host RNA-binding proteins to regulate viral gene expression. Proc Natl Acad Sci USA, 2016, 113(12): 3221-3226.
50.	Dong M, Chen JN, Huang JT, et al. The roles of EBV-encoded microRNAs in EBV-associated tumors. Crit Rev Oncol Hematol, 2019, 135: 30-38.
51.	Vereide DT, Seto E, Chiu YF, et al. Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene, 2014, 33(10): 1258-1264.
52.	Lung RW, Hau PM, Yu KH, et al. EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma. J Pathol, 2018, 244(4): 394-407.

1. Shannon-Lowe C, Rickinson A. The global landscape of EBV-associated tumors. Front Oncol, 2019, 9: 713.
2. Khan G, Hashim MJ. Global burden of deaths from Epstein-Barr virus attributable malignancies 1990-2010. Infect Agent Cancer, 2014, 9(1): 38.
3. Odumade OA, Hogquist KA, Balfour HH Jr. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev, 2011, 24(1): 193-209.
4. Yu J, Liang Q, Wang J, et al. REC8 functions as a tumor suppressor and is epigenetically downregulated in gastric cancer, especially in EBV-positive subtype. Oncogene, 2017, 36(2): 182-193.
5. Dheekollu J, Wiedmer A, Sentana-Lledo D, et al. HCF1 and OCT2 cooperate with EBNA1 to enhance oriP-dependent transcription and episome maintenance of latent Epstein-Barr virus. J Virol, 2016, 90(11): 5353-5367.
6. De Leo A, Calderon A, Lieberman PM. Control of viral latency by episome maintenance proteins. Trends Microbiol, 2020, 28(2): 150-162.
7. Jiang L, Xie C, Lung HL, et al. EBNA1-targeted inhibitors: novel approaches for the treatment of Epstein-Barr virus-associated cancers. Theranostics, 2018, 8(19): 5307-5319.
8. Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer, 2004, 4(10): 757-768.
9. Humme S, Reisbach G, Feederle R, et al. The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold. Proc Natl Acad Sci USA, 2003, 100(19): 10989-10994.
10. Wang L, Tian WD, Xu X, et al. Epstein-Barr virus nuclear antigen 1 (EBNA1) protein induction of epithelial-mesenchymal transition in nasopharyngeal carcinoma cells. Cancer, 2014, 120(3): 363-372.
11. Messick TE, Smith GR, Soldan SS, et al. Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth. Sci Transl Med, 2019, 11(482): eaau5612.
12. Henkel T, Ling PD, Hayward SD, et al. Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. Science, 1994, 265(5168): 92-95.
13. Ling PD, Rawlins DR, Hayward SD. The Epstein-Barr virus immortalizing protein EBNA-2 is targeted to DNA by a cellular enhancer-binding protein. Proc Natl Acad Sci USA, 1993, 90(20): 9237-9241.
14. Lu F, Chen HS, Kossenkov AV, et al. EBNA2 drives formation of new chromosome binding sites and target genes for B-cell master regulatory transcription factors RBP-jκ and EBF1. PLoS Pathog, 2016, 12(1): e1005339.
15. Rabson M, Gradoville L, Heston L, et al. Non-immortalizing P3J-HR-1 Epstein-Barr virus: a deletion mutant of its transforming parent, Jijoye. J Virol, 1982, 44(3): 834-844.
16. Lu F, Wiedmer A, Martin KA, et al. Coordinate regulation of TET2 and EBNA2 controls the DNA methylation state of latent Epstein-Barr virus. J Virol, 2017, 91(20): e00804-17.
17. Anastasiadou E, Stroopinsky D, Alimperti S, et al. Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas. Leukemia, 2019, 33(1): 132-147.
18. Bhattacharjee S, Ghosh Roy S, Bose P, et al. Role of EBNA-3 family proteins in EBV associated B-cell Lymphomagenesis. Front Microbiol, 2016, 7: 457.
19. Maruo S, Zhao B, Johannsen E, et al. Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. Proc Natl Acad Sci USA, 2011, 108(5): 1919-1924.
20. Pei Y, Singh RK, Shukla SK, et al. Epstein-Barr virus nuclear antigen 3C facilitates cell proliferation by regulating cyclin D2. J Virol, 2018, 92(18): e00663-18.
21. Bazot Q, Deschamps T, Tafforeau L, et al. Epstein-Barr virus nuclear antigen 3A protein regulates CDKN2B transcription via interaction with MIZ-1. Nucleic Acids Res, 2014, 42(15): 9700-9716.
22. Styles CT, Paschos K, White RE, et al. The cooperative functions of the EBNA3 proteins are central to EBV persistence and latency. Pathogens, 2018, 7(1): 31.
23. Shukla SK, Jha HC, El-Naccache DW, et al. An EBV recombinant deleted for residues 130-159 in EBNA3C can deregulate p53/Mdm2 and Cyclin D1/CDK6 which results in apoptosis and reduced cell proliferation. Oncotarget, 2016, 7(14): 18116-18134.
24. Zhang S, Pei Y, Lang F, et al. EBNA3C facilitates RASSF1A downregulation through ubiquitin-mediated degradation and promoter hypermethylation to drive B-cell proliferation. PLoS Pathog, 2019, 15(1): e1007514.
25. Bhattacharjee S, Bose P, Patel K, et al. Transcriptional and epigenetic modulation of autophagy promotes EBV oncoprotein EBNA3C induced B-cell survival. Cell Death Dis, 2018, 9(6): 605.
26. Gunnell A, Webb HM, Wood CD, et al. RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth. Nucleic Acids Res, 2016, 44(10): 4636-4650.
27. White RE, Rämer PC, Naresh KN, et al. EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors. J Clin Invest, 2012, 122(4): 1487-1502.
28. Paschos K, Bazot Q, Ho G, et al. Core binding factor (CBF) is required for Epstein-Barr virus EBNA3 proteins to regulate target gene expression. Nucleic Acids Res, 2017, 45(5): 2368-2383.
29. Kang MS, Kieff E. Epstein-Barr virus latent genes. Exp Mol Med, 2015, 47(1): e131.
30. Nakada R, Matsuura Y. Crystal structure of importin-α bound to the nuclear localization signal of Epstein-Barr virus EBNA-LP protein. Protein Sci, 2017, 26(6): 1231-1235.
31. Szymula A, Palermo RD, Bayoumy A, et al. Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naïve B cells, and facilitates recruitment of transcription factors to the viral genome. PLoS Pathog, 2018, 14(2): e1006890.
32. Devergne O, Hatzivassiliou E, Izumi KM, et al. Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activation. Mol Cell Biol, 1996, 16(12): 7098-7108.
33. Luftig M, Prinarakis E, Yasui T, et al. Epstein-Barr virus latent membrane protein 1 activation of NF-kappaB through IRAK1 and TRAF6. Proc Natl Acad Sci USA, 2003, 100(26): 15595-15600.
34. Jiang Y, Yan B, Lai W, et al. Repression of Hox genes by LMP1 in nasopharyngeal carcinoma and modulation of glycolytic pathway genes by HoxC8. Oncogene, 2015, 34(50): 6079-6091.
35. Xiao L, Hu ZY, Dong X, et al. Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy. Oncogene, 2014, 33(37): 4568-4578.
36. Aga M, Bentz GL, Raffa S, et al. Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene, 2014, 33(37): 4613-4622.
37. Meckes DG Jr, Gunawardena HP, Dekroon RM, et al. Modulation of B-cell exosome proteins by gamma herpesvirus infection. Proc Natl Acad Sci USA, 2013, 110(31): E2925-E2933.
38. Hurwitz SN, Nkosi D, Conlon MM, et al. CD63 regulates Epstein-Barr virus LMP1 exosomal packaging, enhancement of vesicle production, and noncanonical NF-κB signaling. J Virol, 2017, 91(5): e02251-16.
39. Incrocci R, McAloon J, Montesano M, et al. Epstein-Barr virus LMP2A utilizes Syk and PI3K to activate NF-κB in B-cell lymphomas to increase MIP-1α production. J Med Virol, 2019, 91(5): 845-855.
40. Rancan C, Schirrmann L, Hüls C, et al. Latent membrane protein LMP2A impairs recognition of EBV-infected cells by CD8⁺ T Cells. PLoS Pathog, 2015, 11(6): e1004906.
41. Minamitani T, Ma Y, Zhou H, et al. Mouse model of Epstein-Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease. Proc Natl Acad Sci USA, 2017, 114(18): 4751-4756.
42. Ma SD, Tsai MH, Romero-Masters JC, et al. Latent membrane protein 1 (LMP1) and LMP2A collaborate to promote Epstein-Barr virus-induced B cell lymphomas in a cord blood-humanized mouse model but are not essential. J Virol, 2017, 91(7): e01928-16.
43. Zhu J, Kamara S, Cen D, et al. Generation of novel affibody molecules targeting the EBV LMP2A N-terminal domain with inhibiting effects on the proliferation of nasopharyngeal carcinoma cells. Cell Death Dis, 2020, 11(4): 213.
44. Ahmed M, Lopez-Albaitero A, Pankov D, et al. TCR-mimic bispecific antibodies targeting LMP2A show potent activity against EBV malignancies. JCI Insight, 2018, 3(4): e97805.
45. Rechsteiner MP, Berger C, Zauner L, et al. Latent membrane protein 2B regulates susceptibility to induction of lytic Epstein-Barr virus infection. J Virol, 2008, 82(4): 1739-1747.
46. Moss WN, Lee N, Pimienta G, et al. RNA families in Epstein-Barr virus. RNA Biol, 2014, 11(1): 10-17.
47. Moss WN, Steitz JA. Genome-wide analyses of Epstein-Barr virus reveal conserved RNA structures and a novel stable intronic sequence RNA. BMC Genomics, 2013, 14: 543.
48. Zerbe CM, Cole JL. Regulation of protein kinase R by Epstein-Barr virus EBER1 RNA. Biochemistry, 2020, 59(12): 1252-1260.
49. Lee N, Yario TA, Gao JS, et al. EBV noncoding RNA EBER2 interacts with host RNA-binding proteins to regulate viral gene expression. Proc Natl Acad Sci USA, 2016, 113(12): 3221-3226.
50. Dong M, Chen JN, Huang JT, et al. The roles of EBV-encoded microRNAs in EBV-associated tumors. Crit Rev Oncol Hematol, 2019, 135: 30-38.
51. Vereide DT, Seto E, Chiu YF, et al. Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene, 2014, 33(10): 1258-1264.
52. Lung RW, Hau PM, Yu KH, et al. EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma. J Pathol, 2018, 244(4): 394-407.

West China Medical Journal

Mechanism of Epstein-Barr virus latent infection-related genes in tumors caused by them

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