Investigating the role of microRNAs, inflammation, and Helicobacter pylori in Epstein-Barr virus associated gastric cancer

Abstract

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a distinct subtype that accounts for nearly 10% of gastric carcinomas. This type of gastric cancer has no relation to any mutation in chromosomal genes, and EBV causes cancer by affecting the epigenetics of host cells through methylation and inactivation of the promoter of tumor suppressor genes. This suggests that EBV infection precedes the clonal growth of EBV-infected cells and subsequently develops carcinoma. Chronic gastritis in the background of EBVaGC might enhance the chance of interaction between gastric epithelial cells and B lymphocytes, and cytokines produced by inflammatory cells might support the growth of EBV-infected gastric epithelial cells. Numerous modifiable risk factors have been identified for gastric cancer (GC). Inflammation is a complicated host immune response to biological, chemical, and physical invasions. Chronic inflammation, which is caused by genetic mutations, autoimmune diseases, constant exposure to environmental factors, and viral infections, can significantly increase the risk of cancer. According to epidemiologic studies, chronic infection and inflammation are considered the main risk factors for different types of cancer. Furthermore, although oncogenic viruses stimulate inflammation by dint of different mechanisms, they generally activate certain signaling pathways, including NF-κB and STAT3, in charge of cancer development. The role of EBV in chronic gastric inflammation has received little attention. However, several studies have indicated EBV as well as Helicobacter pylori to be initially involved in the oncogenic process of gastric cancer by increasing chronic inflammation and tissue damage. Moreover, other risk factors including lifestyle and HPV infection play a role in the progress of gastric cancer.

Keywords

• Epstein Barr Virus
• Helicobacter Pylori
• Gastric cancer
• Inflammation
• MicroRNA

References

1. 1. Rawla, P. and A. Barsouk, Epidemiology of gastric cancer: global trends, risk factors and prevention. Przeglad gastroenterologiczny, 2019. 14(1): p. 26.
2. 2. van den Brandt, P.A., The impact of a healthy lifestyle on the risk of esophageal and gastric cancer subtypes. European Journal of Epidemiology, 2022: p. 1-15.
3. 3. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA: a cancer journal for clinicians, 2016. 66(1): p. 7-30.
4. 4. Calcagno, D.Q., et al., MYC and gastric adenocarcinoma carcinogenesis. World journal of gastroenterology: WJG, 2008. 14(39): p. 5962.
5. 5. Feil, R. and M.F. Fraga, Epigenetics and the environment: emerging patterns and implications. Nature Reviews Genetics, 2012. 13(2): p. 97.
6. 6. Mohebbi, M., et al., Geographical spread of gastrointestinal tract cancer incidence in the Caspian Sea region of Iran: spatial analysis of cancer registry data. BMC cancer, 2008. 8(1): p. 137.
7. 7. Young, L.S. and A.B. Rickinson, Epstein–Barr virus: 40 years on. Nature Reviews Cancer, 2004. 4(10): p. 757.
8. 8. Silver, B., J. Krell, and A.E. Frampton, Do miRNAs hold the key to controlling EBV-driven tumorigenesis? Future Virology, 2012. 7(11): p. 1045-1049.

9. 9. Delecluse, H.-J., et al., Propagation and recovery of intact, infectious Epstein–Barr virus from prokaryotic to human cells. Proceedings of the National Academy of Sciences, 1998. 95(14): p. 8245-8250.
10. 10. Feng, W.-h., et al., ZEB1 and c-Jun levels contribute to the establishment of highly lytic Epstein-Barr virus infection in gastric AGS cells. Journal of virology, 2007. 81(18): p. 10113-10122.
11. 11. Babcock, G.J., E.M. Miyashita-Lin, and D.A. Thorley-Lawson, Detection of EBV Infection at the Single-Cell Level, in Epstein-Barr Virus Protocols. 2001, Springer. p. 103-110.
12. 12. Babcock, G.J., et al., EBV persistence in memory B cells in vivo. Immunity, 1998. 9(3): p. 395-404.
13. 13. Cárdenas-Mondragón, M.G., et al., Epstein Barr virus and Helicobacter pylori co-infection are positively associated with severe gastritis in pediatric patients. PloS one, 2013. 8(4): p. e62850.
14. 14. Naseem, M., et al., Outlooks on Epstein-Barr virus associated gastric cancer. Cancer treatment reviews, 2018. 66: p. 15-22.
15. 15. Şenol, K., et al., The role of inflammation in gastric cancer, in Inflammation and Cancer. 2014, Springer. p. 235-257.
16. 16. Ida, S., M. Watanabe, and H. Baba, Chronic inflammation and gastrointestinal cancer. Journal of Cancer Metastasis and Treatment, 2015. 1(3): p. 138.
17. 17. Joshi, S.S. and B.D. Badgwell, Current treatment and recent progress in gastric cancer. CA: a cancer journal for clinicians, 2021. 71(3): p. 264-279.
18. 18. Esquela-Kerscher, A. and F.J. Slack, Oncomirs—microRNAs with a role in cancer. Nature reviews cancer, 2006. 6(4): p. 259.
19. 19. Zhang, J., et al., The oncogenic role of Epstein–Barr virus‐encoded micro RNA s in Epstein–Barr virus‐associated gastric carcinoma. Journal of cellular and molecular medicine, 2018. 22(1): p. 38-45.
20. 20. Read, S.A. and M.W. Douglas, Virus induced inflammation and cancer development. Cancer letters, 2014. 345(2): p. 174-181.
21. 21. Perwez Hussain, S. and C.C. Harris, Inflammation and cancer: an ancient link with novel potentials. International journal of cancer, 2007. 121(11): p. 2373-2380.
22. 22. Hussain, S.P., L.J. Hofseth, and C.C. Harris, Radical causes of cancer. Nature Reviews Cancer, 2003. 3(4): p. 276.
23. 23. Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. cell, 2011. 144(5): p. 646-674.
24. 24. Sica, A., et al. Macrophage polarization in tumour progression. in Seminars in cancer biology. 2008. Elsevier.
25. 25. Shiva, A. and S. Arab, The effect of inflammation on presence of cancer. J of clin exc, 2015. 4(1): p. 57-67.
26. 26. Kuraishy, A., M. Karin, and S.I. Grivennikov, Tumor promotion via injury-and death-induced inflammation. Immunity, 2011. 35(4): p. 467-477.
27. 27. Moore, P.S. and Y. Chang, Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nature reviews cancer, 2010. 10(12): p. 878.
28. 28. Fan, Y., R. Mao, and J. Yang, NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein & cell, 2013. 4(3): p. 176-185.
29. 29. Chiba, T., H. Marusawa, and T. Ushijima, Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology, 2012. 143(3): p. 550-563.
30. 30. Sokolova, O. and M. Naumann, NF‐κB signaling in gastric cancer. Toxins, 2017. 9(4): p. 119.
31. 31. Yu, H., D. Pardoll, and R. Jove, STATs in cancer inflammation and immunity: a leading role for STAT3. Nature reviews cancer, 2009. 9(11): p. 798-809.
32. 32. Pinlaor, S., et al., Repeated infection with Opisthorchis viverrini induces accumulation of 8-nitroguanine and 8-oxo-7, 8-dihydro-2′-deoxyguanine in the bile duct of hamsters via inducible nitric oxide synthase. Carcinogenesis, 2004. 25(8): p. 1535-1542.
33. 33. Ohnishi, S., et al., DNA damage in inflammation-related carcinogenesis and cancer stem cells. Oxidative medicine and cellular longevity, 2013. 2013.
34. 34. Murata, M., Inflammation and cancer. Environmental health and preventive medicine, 2018. 23(1): p. 50.
35. 35. Pfeifer, G., Defining driver DNA methylation changes in human cancer. International journal of molecular sciences, 2018. 19(4): p. 1166.
36. 36. Maekita, T., et al., High levels of aberrant DNA methylation in Helicobacter pylori–infected gastric mucosae and its possible association with gastric cancer risk. Clinical Cancer Research, 2006. 12(3): p. 989-995.
37. 37. de Souza, C.R.T., et al., Occurrence of Helicobacter pylori and Epstein-Barr virus infection in endoscopic and gastric cancer patients from Northern Brazil. BMC gastroenterology, 2014. 14(1): p. 179.
38. 38. Yip, Y.L., et al., Efficient immortalization of primary nasopharyngeal epithelial cells for EBV infection study. PLoS One, 2013. 8(10): p. e78395.
39. 39. Akhter, S., et al., Epstein–Barr virus and human hepatocellular carcinoma. Cancer letters, 2003. 192(1): p. 49-57.
40. 40. Young, L., et al., Expression of Epstein–Barr virus transformation–associated genes in tissues of patients with EBV lymphoproliferative disease. New England Journal of Medicine, 1989. 321(16): p. 1080-1085.
41. 41. Singh, S. and H.C. Jha, Status of Epstein-Barr virus coinfection with Helicobacter pylori in gastric cancer. Journal of oncology, 2017. 2017.
42. 42. Tsao, S.W., et al. The biology of EBV infection in human epithelial cells. in Seminars in cancer biology. 2012. Elsevier.
43. 43. Hess, R.D., Routine Epstein-Barr virus diagnostics from the laboratory perspective: still challenging after 35 years. Journal of clinical microbiology, 2004. 42(8): p. 3381-3387.
44. 44. Gan, Y., et al., Epithelial cell polarization is a determinant in the infectious outcome of immunoglobulin A-mediated entry by Epstein-Barr virus. Journal of virology, 1997. 71(1): p. 519-526.
45. 45. Babcock, G.J., et al., Epstein-Barr virus–infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients. Journal of Experimental Medicine, 1999. 190(4): p. 567-576.
46. 46. Szakonyi, G., et al., Structure of the Epstein-Barr virus major envelope glycoprotein. Nature structural & molecular biology, 2006. 13(11): p. 996.
47. 47. Hutt-Fletcher, L.M., Epstein-Barr virus entry. Journal of virology, 2007. 81(15): p. 7825-7832.
48. 48. Kim, H., H. Choi, and S.K. Lee, Epstein-Barr virus microRNA miR-BART20-5p suppresses lytic induction by inhibiting BAD-mediated caspase-3-dependent apoptosis. Journal of virology, 2016. 90(3): p. 1359-1368.
49. 49. Tugizov, S.M., J.W. Berline, and J.M. Palefsky, Epstein-Barr virus infection of polarized tongue and nasopharyngeal epithelial cells. Nature medicine, 2003. 9(3): p. 307.
50. 50. Gulley, M.L., et al., Epstein-Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. Human pathology, 1996. 27(1): p. 20-27.
51. 51. Yau, T.O., C.-M. Tang, and J. Yu, Epigenetic dysregulation in Epstein-Barr virus-associated gastric carcinoma: disease and treatments. World Journal of Gastroenterology: WJG, 2014. 20(21): p. 6448.
52. 52. Matsusaka, K., et al., Classification of Epstein–Barr virus–positive gastric cancers by definition of DNA methylation epigenotypes. Cancer research, 2011. 71(23): p. 7187-7197.
53. 53. Sugiura, M., et al., Transcriptional analysis of Epstein-Barr virus gene expression in EBV-positive gastric carcinoma: unique viral latency in the tumour cells. British journal of cancer, 1996. 74(4): p. 625.
54. 54. Niedobitek, G., et al., Epstein–Barr virus (EBV) infection in infectious mononucleosis: virus latency, replication and phenotype of EBV‐infected cells. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland, 1997. 182(2): p. 151-159.
55. 55. Dawson, C.W., R.J. Port, and L.S. Young. The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). in Seminars in cancer biology. 2012. Elsevier.
56. 56. Tegtmeyer, N., S. Wessler, and S. Backert, Role of the cag‐pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. The FEBS journal, 2011. 278(8): p. 1190-1202.
57. 57. Giudice, A., et al., Role of viral miRNAs and epigenetic modifications in Epstein-Barr Virus-associated gastric carcinogenesis. Oxidative medicine and cellular longevity, 2016. 2016.
58. 58. zur Hausen, A., et al., Unique transcription pattern of Epstein-Barr virus (EBV) in EBV-carrying gastric adenocarcinomas: expression of the transforming BARF1 gene. Cancer Research, 2000. 60(10): p. 2745-2748.
59. 59. Chang, M.S., et al., Epstein-Barr virus-encoded BARF1 promotes proliferation of gastric carcinoma cells through regulation of NF-κB. Journal of virology, 2013. 87(19): p. 10515-10523.
60. 60. Thompson, S., et al., Development of a high-throughput screen for inhibitors of Epstein-Barr virus EBNA1. Journal of biomolecular screening, 2010. 15(9): p. 1107-1115.
61. 61. Li, N., et al., Discovery of selective inhibitors against EBNA1 via high throughput in silico virtual screening. PloS one, 2010. 5(4): p. e10126.
62. 62. Iizasa, H., et al., Epstein-Barr Virus (EBV)-associated gastric carcinoma. Viruses, 2012. 4(12): p. 3420-3439.
63. 63. Shinozaki-Ushiku, A., A. Kunita, and M. Fukayama, Update on Epstein-Barr virus and gastric cancer. International journal of oncology, 2015. 46(4): p. 1421-1434.
64. 64. Banerjee, A.S., A.D. Pal, and S. Banerjee, Epstein–Barr virus-encoded small non-coding RNAs induce cancer cell chemoresistance and migration. Virology, 2013. 443(2): p. 294-305.
65. 65. Nanbo, A. and K. Takada, The role of Epstein–Barr virus‐encoded small RNAs (EBERs) in oncogenesis. Reviews in medical virology, 2002. 12(5): p. 321-326.
66. 66. Lipson, E.J., et al. Antagonists of PD-1 and PD-L1 in cancer treatment. in Seminars in oncology. 2015. Elsevier.
67. 67. Chen, J., X.D. Zhang, and C. Proud, Dissecting the signaling pathways that mediate cancer in PTEN and LKB1 double-knockout mice. Sci. Signal., 2015. 8(392): p. pe1-pe1.
68. 68. Chong, J.M., et al., Expression of CD44 variants in gastric carcinoma with or without Epstein‐Barr virus. International journal of cancer, 1997. 74(4): p. 450-454.
69. 69. Saiki, Y., et al., Immunophenotypic characterization of Epstein-Barr virus-associated gastric carcinoma: massive infiltration by proliferating CD8+ T-lymphocytes. Laboratory investigation; a journal of technical methods and pathology, 1996. 75(1): p. 67-76.
70. 70. Song, H.J., et al., Host inflammatory response predicts survival of patients with Epstein-Barr virus–associated gastric carcinoma. Gastroenterology, 2010. 139(1): p. 84-92. e2.
71. 71. Iwasaki, Y., et al., Establishment and characterization of a human Epstein-Barr virus-associated gastric carcinoma in SCID mice. Journal of virology, 1998. 72(10): p. 8321-8326.
72. 72. Chong, J.-M., et al., Interleukin-1β expression in human gastric carcinoma with Epstein-Barr virus infection. Journal of virology, 2002. 76(13): p. 6825-6831.
73. 73. Fukayama, M., R. Hino, and H. Uozaki, Epstein–Barr virus and gastric carcinoma: virus–host interactions leading to carcinoma. Cancer science, 2008. 99(9): p. 1726-1733.
74. 74. Kuzushima, K., et al., Increased frequency of antigen-specific CD8+ cytotoxic T lymphocytes infiltrating an Epstein-Barr virus–associated gastric carcinoma. The Journal of clinical investigation, 1999. 104(2): p. 163-171.
75. 75. Morales-Sanchez, A. and E. M Fuentes-Panana, Epstein-Barr virus-associated gastric cancer and potential mechanisms of oncogenesis. Current cancer drug targets, 2017. 17(6): p. 534-554.
76. 76. Alinezhad, F., et al., Evidence of Epstein–Barr Virus in Female Breast Cancer. Iranian Journal of Public Health, 2021. 50(2): p. 425-427.
77. 77. Huang, T., et al., SNHG8 is identified as a key regulator of epstein-barr virus (EBV)-associated gastric cancer by an integrative analysis of lncRNA and mRNA expression. Oncotarget, 2016. 7(49): p. 80990.
78. 78. Shinozaki, A., et al., Downregulation of microRNA-200 in EBV-associated gastric carcinoma. Cancer Research, 2010. 70(11): p. 4719-4727.
79. 79. Shinozaki-Ushiku, A., et al., Profiling of virus-encoded microRNAs in Epstein-Barr virus-associated gastric carcinoma and their roles in gastric carcinogenesis. Journal of virology, 2015. 89(10): p. 5581-5591.
80. 80. Qiu, J., et al., A novel persistence associated EBV miRNA expression profile is disrupted in neoplasia. PLoS pathogens, 2011. 7(8): p. e1002193.
81. 81. Kim, H., H. Choi, and S.K. Lee, Epstein–Barr virus miR-BART20-5p regulates cell proliferation and apoptosis by targeting BAD. Cancer letters, 2015. 356(2): p. 733-742.
82. 82. Kang, D., R.L. Skalsky, and B.R. Cullen, EBV BART microRNAs target multiple pro-apoptotic cellular genes to promote epithelial cell survival. PLoS pathogens, 2015. 11(6): p. e1004979.
83. 83. Iizasa, H., et al., Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency. Journal of Biological Chemistry, 2010. 285(43): p. 33358-33370.
84. 84. Piscione, M., et al., Eradication of Helicobacter pylori and gastric cancer: a controversial relationship. Frontiers in Microbiology, 2021. 12: p. 630852.
85. 85. Shirgir, S., P. Ghotaslou, and R. Ghotaslou, The Presence of Helicobacter Pylori DNA in Coronary Artery Diseases (CAD). 2021.
86. 86. Ren, S., et al., Prevalence of Helicobacter pylori infection in China: A systematic review and meta‐analysis. Journal of Gastroenterology and Hepatology, 2022. 37(3): p. 464-470.
87. 87. Alfarouk, K.O., et al., The possible role of Helicobacter pylori in gastric cancer and its management. Frontiers in oncology, 2019. 9: p. 75.
88. 88. Oster, P., et al., Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies. Gut, 2022. 71(3): p. 457-466.
89. 89. Cárdenas-Mondragón, M., et al., Case–control study of Epstein–Barr virus and Helicobacter pylori serology in Latin American patients with gastric disease. British journal of cancer, 2015. 112(12): p. 1866.
90. 90. Shukla, S., et al., Expression profile of latent and lytic transcripts of epstein–barr virus in patients with gastroduodenal diseases: a study from northern India. Journal of medical virology, 2012. 84(8): p. 1289-1297.
91. 91. Minoura-Etoh, J., et al., Helicobacter pylori-associated oxidant monochloramine induces reactivation of Epstein–Barr virus (EBV) in gastric epithelial cells latently infected with EBV. Journal of medical microbiology, 2006. 55(7): p. 905-911.
92. 92. Hirano, A., et al., Evaluation of Epstein-Barr virus DNA load in gastric mucosa with chronic atrophic gastritis using a real-time quantitative PCR assay. International journal of gastrointestinal cancer, 2003. 34(2-3): p. 87-94.
93. 93. Matsusaka, K., et al., DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus. World Journal of Gastroenterology: WJG, 2014. 20(14): p. 3916.
94. 94. Martínez-Carrillo, D., et al., Helicobacter pylori vacA and cagA genotype diversity and interferon gamma expression in patients with chronic gastritis and patients with gastric cancer. Revista de Gastroenterología de México (English Edition), 2014. 79(4): p. 220-228.
95. 95. Noach, L., et al., Mucosal tumor necrosis factor-or, interleukin-1/3, and interleukin-8 production in patients with helicobacter pylori infection. Scandinavian journal of gastroenterology, 1994. 29(5): p. 425-429.
96. 96. Yamaoka, Y., et al., Helicobacter pylori cagA gene and expression of cytokine messenger RNA in gastric mucosa. Gastroenterology, 1996. 110(6): p. 1744-1752.
97. 97. El-Omar, E.M., et al., Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology, 2003. 124(5): p. 1193-1201.
98. 98. Churin, Y., et al., Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol, 2003. 161(2): p. 249-255.
99. 99. Brandt, S., et al., Helicobacter pylori activates protein kinase C delta to control Raf in MAP kinase signalling: role in AGS epithelial cell scattering and elongation. Cell motility and the cytoskeleton, 2009. 66(10): p. 874-892.
100. 100. Vallejo-Flores, G., et al., Helicobacter pylori CagA suppresses apoptosis through activation of AKT in a nontransformed epithelial cell model of glandular acini formation. BioMed research international, 2015. 2015.
101. 101. Pilon, N., et al., Wnt signaling is a key mediator of Cdx1 expression in vivo. Development, 2007. 134(12): p. 2315-2323.
102. 102. YU, X.W., et al., Helicobacter pylori induces malignant transformation of gastric epithelial cells in vitro. Apmis, 2011. 119(3): p. 187-197.
103. 103. Shukla, S.K., et al., Transforming growth factor beta 1 (TGF-β1) modulates Epstein-Barr virus reactivation in absence of Helicobacter pylori infection in patients with gastric cancer. Cytokine, 2016. 77: p. 176-179.
104. 104. Sadeghian, Z., et al., Prevalence of Human Papillomavirus Infection in Gastric Cancer in Ardebil Province, Northwest of Iran. Iranian Journal of Virology, 2022. 16(1): p. 28-35.
105. 105. Baj, J., et al., The Involvement of Human Papilloma Virus in Gastrointestinal Cancers. Cancers, 2022. 14(11): p. 2607.
106. 106. Jafari-Sales, A., et al., The Presence of Human Papillomavirus and Epstein-Barr Virus Infection in Gastric Cancer: A Systematic Study.
107. 107. Zeng, Z.-m., et al., Human papillomavirus as a potential risk factor for gastric cancer: a meta-analysis of 1,917 cases. OncoTargets and therapy, 2016. 9: p. 7105.
108. 108. Snietura, M., et al., Potential role of human papilloma virus in the pathogenesis of gastric cancer. World Journal of Gastroenterology: WJG, 2014. 20(21): p. 6632.
109. 109. Kawazoe, A., et al., Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein–Barr virus status in a large cohort of gastric cancer patients. Gastric Cancer, 2017. 20(3): p. 407-415.
110. 110. Derks, S., et al., Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers. Oncotarget, 2016. 7(22): p. 32925.
111. 111. Cech, T.R. and J.A. Steitz, The noncoding RNA revolution—trashing old rules to forge new ones. Cell, 2014. 157(1): p. 77-94.
112. 112. Vavouri, T. and B. Lehner, Human genes with CpG island promoters have a distinct transcription-associated chromatin organization. Genome biology, 2012. 13(11): p. R110.
113. 113. Padmanabhan, N., T. Ushijima, and P. Tan, How to stomach an epigenetic insult: the gastric cancer epigenome. Nature Reviews Gastroenterology & Hepatology, 2017. 14(8): p. 467.
114. 114. Kang, G.H., et al., Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. The American journal of pathology, 2002. 160(3): p. 787-794.
115. 115. Chong, J.M., et al., Global and non‐random CpG‐island methylation in gastric carcinoma associated with Epstein‐Barr virus. Cancer science, 2003. 94(1): p. 76-80.
116. 116. Etoh, T., et al., Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. The American journal of pathology, 2004. 164(2): p. 689-699.
117. 117. Chang, M.-S., et al., CpG island methylation status in gastric carcinoma with and without infection of Epstein-Barr virus. Clinical Cancer Research, 2006. 12(10): p. 2995-3002.
118. 118. Zhao, J., et al., Genome‐wide identification of Epstein‐Barr virus–driven promoter methylation profiles of human genes in gastric cancer cells. Cancer, 2013. 119(2): p. 304-312.
119. 119. Kong, Q.-L., et al., Epstein-Barr virus-encoded LMP2A induces an epithelial–mesenchymal transition and increases the number of side population stem-like cancer cells in nasopharyngeal carcinoma. PLoS pathogens, 2010. 6(6): p. e1000940.
120. 120. Li, L., et al., Oncogenic induction of cellular high CpG methylation by Epstein-Barr virus in malignant epithelial cells. Chinese journal of cancer, 2014. 33(12): p. 604.
121. 121. Moody, C.A., et al., Modulation of the cell growth regulator mTOR by Epstein-Barr virus-encoded LMP2A. Journal of virology, 2005. 79(9): p. 5499-5506.
122. 122. Pegtel, D.M., et al., Epstein-Barr-virus-encoded LMP2A induces primary epithelial cell migration and invasion: possible role in nasopharyngeal carcinoma metastasis. Journal of virology, 2005. 79(24): p. 15430-15442.
123. 123. Kida, Y., K. Miyauchi, and Y. Takano, Gastric adenocarcinoma with differentiation to sarcomatous components associated with monoclonal Epstein-Barr virus infection and LMP-1 expression. Virchows Archiv A, 1993. 423(5): p. 383-387.
124. 124. Wang, Q., et al., Anti-apoptotic role of BARF1 in gastric cancer cells. Cancer letters, 2006. 238(1): p. 90-103.
125. 125. Buschle, A. and W. Hammerschmidt. Epigenetic lifestyle of Epstein-Barr virus. in Seminars in Immunopathology. 2020. Springer.
126. 126. Nishikawa, J., et al., The role of epigenetic regulation in Epstein-Barr virus-Associated gastric cancer. International journal of molecular sciences, 2017. 18(8): p. 1606.
127. 127. Bouras, E., et al., Diet and Risk of Gastric Cancer: An Umbrella Review. Nutrients, 2022. 14(9): p. 1764.
128. 128. Hashemi Amin, F., et al., A Geospatial database of gastric cancer patients and associated potential risk factors including lifestyle and air pollution. BMC Research Notes, 2021. 14(1): p. 1-3.
129. 129. Ishikura, N., et al., Risk Prediction for Gastric Cancer Using GWAS-Identifie Polymorphisms, Helicobacter pylori Infection and Lifestyle-Related Risk Factors in a Japanese Population. Cancers, 2021. 13(21): p. 5525.
130. 130. Shiao, Y.-H., et al., p53 alteration in gastric precancerous lesions. The American journal of pathology, 1994. 144(3): p. 511.
131. 131. Ojima, H., et al., Infrequent overexpression of p53 protein in Epstein‐Barr virus‐associated gastric carcinomas. Japanese journal of cancer research, 1997. 88(3): p. 262-266.
132. 132. Akiba, S., et al., Epstein‐Barr virus associated gastric carcinoma: Epidemiological and clinicopathological features. Cancer science, 2008. 99(2): p. 195-201.
133. 133. Sasaki, S., et al., EBV-associated gastric cancer evades T-cell immunity by PD-1/PD-L1 interactions. Gastric Cancer, 2019. 22(3): p. 486-496.
134. 134. Kang, Y.-K., et al., Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet, 2017. 390(10111): p. 2461-2471.
135. 135. Fukayama, M. and T. Ushiku, Epstein-Barr virus-associated gastric carcinoma. Pathology-Research and Practice, 2011. 207(9): p. 529-537.
136. 136. Li, N., et al., Discovery of selective inhibitors against EBNA1 via high throughput in silico virtual screening. PloS one, 2010. 5(4).
137. 137. Nishikawa, J., et al., Clinical Importance of Epstein–Barr Virus-Associated Gastric Cancer. Cancers, 2018. 10(6): p. 167.
138. 138. Camargo, M.C., et al., Improved survival of gastric cancer with tumour Epstein–Barr virus positivity: an international pooled analysis. Gut, 2014. 63(2): p. 236-243.