Gastric Carcinogenesis

  • Hitoshi Tsugawa
  • Hidekazu SuzukiEmail author


Gastric cancer is a leading cause of cancer-related death, particularly in Asia. A number of risk factors associated with gastric carcinogenesis have been identified by epidemiological, clinical, and molecular studies. Several epigenetic and proteomic modulations are known to be primary drivers promoting carcinogenesis and the progression of gastric cancer. In recent years, the role of these modulations in gastric carcinogenesis has been widely studied. Early gastric cancer can be treated and even completely cured surgically using endoscopic submucosal dissection (ESD). However, the prognosis of advanced or distantly metastasized gastric cancer is poor. Highly advanced gastric cancer is difficult to completely cure using chemotherapy. Therefore, prevention or early detection of gastric cancer is crucial. Understanding how epigenetic or proteomic modulations affect gastric carcinogenesis has importance in detecting, treating, and preventing gastric cancer. Further study is expected to provide us the basis for targeted molecular therapy or novel biomarkers that evaluate the prognosis or risk of gastric carcinogenesis. In this chapter, recent results of studies on epigenetic and proteomic modulations related to gastric carcinogenesis and clinical outcomes are described, with a special focus on Japanese research.


Helicobacter pylori Inflammation Epstein-Barr virus (EBV) Epigenetic modulation miRNA 


  1. 1.
    Ono H, Yao K, Fujishiro M, Oda I, Nimura S, Yahagi N, et al. Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer. Dig Endosc. 2016;28(1):3–15.CrossRefGoogle Scholar
  2. 2.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.CrossRefGoogle Scholar
  3. 3.
    Montecucco C, Rappuoli R. Living dangerously: how Helicobacter pylori survives in the human stomach. Nat Rev Mol Cell Biol. 2001;2(6):457–66.CrossRefGoogle Scholar
  4. 4.
    Kim MK, Sasaki S, Sasazuki S, Tsugane S, Japan Public Health Center-based Prospective Study G. Prospective study of three major dietary patterns and risk of gastric cancer in Japan. Int J Cancer. 2004;110(3):435–42.CrossRefGoogle Scholar
  5. 5.
    Nishino Y, Inoue M, Tsuji I, Wakai K, Nagata C, Mizoue T, et al. Tobacco smoking and gastric cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol. 2006;36(12):800–7.CrossRefGoogle Scholar
  6. 6.
    Soffritti M, Belpoggi F, Cevolani D, Guarino M, Padovani M, Maltoni C. Results of long-term experimental studies on the carcinogenicity of methyl alcohol and ethyl alcohol in rats. Ann N Y Acad Sci. 2002;982:46–69.CrossRefGoogle Scholar
  7. 7.
    Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, et al. Carcinogenicity of alcoholic beverages. Lancet Oncol. 2007;8(4):292–3.CrossRefGoogle Scholar
  8. 8.
    Moy KA, Fan Y, Wang R, Gao YT, Yu MC, Yuan JM. Alcohol and tobacco use in relation to gastric cancer: a prospective study of men in Shanghai, China. Cancer Epidemiol Biomark Prev. 2010;19(9):2287–97.CrossRefGoogle Scholar
  9. 9.
    Duell EJ, Travier N, Lujan-Barroso L, Clavel-Chapelon F, Boutron-Ruault MC, Morois S, et al. Alcohol consumption and gastric cancer risk in the European prospective investigation into cancer and nutrition (EPIC) cohort. Am J Clin Nutr. 2011;94(5):1266–75.CrossRefGoogle Scholar
  10. 10.
    Murata M, Takayama K, Choi BC, Pak AW. A nested case-control study on alcohol drinking, tobacco smoking, and cancer. Cancer Detect Prev. 1996;20(6):557–65.PubMedGoogle Scholar
  11. 11.
    Inoue M, Tajima K, Kobayashi S, Suzuki T, Matsuura A, Nakamura T, et al. Protective factor against progression from atrophic gastritis to gastric cancer—data from a cohort study in Japan. Int J Cancer. 1996;66(3):309–14.CrossRefGoogle Scholar
  12. 12.
    Fujino Y, Tamakoshi A, Ohno Y, Mizoue T, Tokui N, Yoshimura T, et al. Prospective study of educational background and stomach cancer in Japan. Prev Med. 2002;35(2):121–7.CrossRefGoogle Scholar
  13. 13.
    Sauvaget C, Lagarde F, Nagano J, Soda M, Koyama K, Kodama K. Lifestyle factors, radiation and gastric cancer in atomic-bomb survivors (Japan). Cancer Causes Control. 2005;16(7):773–80.CrossRefGoogle Scholar
  14. 14.
    Tamura T, Wada K, Tsuji M, Konishi K, Kawachi T, Hori A, et al. Association of alcohol consumption with the risk of stomach cancer in a Japanese population: a prospective cohort study. Eur J Cancer Prev. 2016;27(1):27–32.CrossRefGoogle Scholar
  15. 15.
    Matsuo K, Oze I, Hosono S, Ito H, Watanabe M, Ishioka K, et al. The aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism interacts with alcohol drinking in the risk of stomach cancer. Carcinogenesis. 2013;34(7):1510–5.CrossRefGoogle Scholar
  16. 16.
    Agarwal DP, Goedde HW. Pharmacogenetics of alcohol metabolism and alcoholism. Pharmacogenetics. 1992;2(2):48–62.CrossRefGoogle Scholar
  17. 17.
    Takeshita T, Morimoto K, Mao XQ, Hashimoto T, Furuyama J. Phenotypic differences in low Km aldehyde dehydrogenase in Japanese workers. Lancet. 1993;341(8848):837–8.CrossRefGoogle Scholar
  18. 18.
    Sonohara F, Inokawa Y, Hayashi M, Kodera Y, Nomoto S. Epigenetic modulation associated with carcinogenesis and prognosis of human gastric cancer. Oncol Lett. 2017;13(5):3363–8.CrossRefGoogle Scholar
  19. 19.
    Cai L, Ma X, Huang Y, Zou Y, Chen X. Aberrant histone methylation and the effect of Suv39H1 siRNA on gastric carcinoma. Oncol Rep. 2014;31(6):2593–600.CrossRefGoogle Scholar
  20. 20.
    Issa JP. Aging and epigenetic drift: a vicious cycle. J Clin Invest. 2014;124(1):24–9.CrossRefGoogle Scholar
  21. 21.
    Kang GH, Lee HJ, Hwang KS, Lee S, Kim JH, Kim JS. Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation. Am J Pathol. 2003;163(4):1551–6.CrossRefGoogle Scholar
  22. 22.
    Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345(11):784–9.CrossRefGoogle Scholar
  23. 23.
    Maekita T, Nakazawa K, Mihara M, Nakajima T, Yanaoka K, Iguchi M, et al. High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res. 2006;12(3 Pt 1):989–95.CrossRefGoogle Scholar
  24. 24.
    Zou XP, Zhang B, Zhang XQ, Chen M, Cao J, Liu WJ. Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions. Hum Pathol. 2009;40(11):1534–42.CrossRefGoogle Scholar
  25. 25.
    Uemura N, Mukai T, Okamoto S, Yamaguchi S, Mashiba H, Taniyama K, et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomark Prev. 1997;6(8):639–42.Google Scholar
  26. 26.
    Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet. 2008;372(9636):392–7.CrossRefGoogle Scholar
  27. 27.
    Asaka M, Mabe K, Matsushima R, Tsuda M. Helicobacter pylori eradication to eliminate gastric cancer: the Japanese strategy. Gastroenterol Clin N Am. 2015;44(3):639–48.CrossRefGoogle Scholar
  28. 28.
    Chan AO, Peng JZ, Lam SK, Lai KC, Yuen MF, Cheung HK, et al. Eradication of Helicobacter pylori infection reverses E-cadherin promoter hypermethylation. Gut. 2006;55(4):463–8.CrossRefGoogle Scholar
  29. 29.
    Shin CM, Kim N, Lee HS, Park JH, Ahn S, Kang GH, et al. Changes in aberrant DNA methylation after Helicobacter pylori eradication: a long-term follow-up study. Int J Cancer. 2013;133(9):2034–42.CrossRefGoogle Scholar
  30. 30.
    Kamada T, Hata J, Sugiu K, Kusunoki H, Ito M, Tanaka S, et al. Clinical features of gastric cancer discovered after successful eradication of helicobacter pylori: results from a 9-year prospective follow-up study in Japan. Aliment Pharmacol Ther. 2005;21(9):1121–6.CrossRefGoogle Scholar
  31. 31.
    Yamamoto K, Kato M, Takahashi M, Haneda M, Shinada K, Nishida U, et al. Clinicopathological analysis of early-stage gastric cancers detected after successful eradication of Helicobacter pylori. Helicobacter. 2011;16(3):210–6.CrossRefGoogle Scholar
  32. 32.
    Nakajima T, Enomoto S, Yamashita S, Ando T, Nakanishi Y, Nakazawa K, et al. Persistence of a component of DNA methylation in gastric mucosae after Helicobacter pylori eradication. J Gastroenterol. 2010;45(1):37–44.CrossRefGoogle Scholar
  33. 33.
    Tahara S, Tahara T, Tuskamoto T, Horiguchi N, Kawamura T, Okubo M, et al. Morphologic characterization of residual DNA methylation in the gastric mucosa after Helicobacter pylori eradication. Cancer Med. 2017;6(7):1730–7.CrossRefGoogle Scholar
  34. 34.
    Takahashi I, Matsusaka T, Onohara T, Nishizaki T, Ishikawa T, Tashiro H, et al. Clinicopathological features of long-term survivors of scirrhous gastric cancer. Hepato-Gastroenterology. 2000;47(35):1485–8.PubMedGoogle Scholar
  35. 35.
    De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97–110.CrossRefGoogle Scholar
  36. 36.
    van Kouwenhove M, Kedde M, Agami R. MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat Rev Cancer. 2011;11(9):644–56.CrossRefGoogle Scholar
  37. 37.
    Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 2008;283(22):14910–4.CrossRefGoogle Scholar
  38. 38.
    Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601.CrossRefGoogle Scholar
  39. 39.
    Kurashige J, Kamohara H, Watanabe M, Hiyoshi Y, Iwatsuki M, Tanaka Y, et al. MicroRNA-200b regulates cell proliferation, invasion, and migration by directly targeting ZEB2 in gastric carcinoma. Ann Surg Oncol. 2012;19(Suppl 3):S656–64.CrossRefGoogle Scholar
  40. 40.
    Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 2009;11(12):1487–95.CrossRefGoogle Scholar
  41. 41.
    Yu J, Ohuchida K, Mizumoto K, Sato N, Kayashima T, Fujita H, et al. MicroRNA, hsa-miR-200c, is an independent prognostic factor in pancreatic cancer and its upregulation inhibits pancreatic cancer invasion but increases cell proliferation. Mol Cancer. 2010;9:169.CrossRefGoogle Scholar
  42. 42.
    Xia H, Cheung WK, Sze J, Lu G, Jiang S, Yao H, et al. miR-200a regulates epithelial-mesenchymal to stem-like transition via ZEB2 and beta-catenin signaling. J Biol Chem. 2010;285(47):36995–7004.CrossRefGoogle Scholar
  43. 43.
    Davalos V, Moutinho C, Villanueva A, Boque R, Silva P, Carneiro F, et al. Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis. Oncogene. 2012;31(16):2062–74.CrossRefGoogle Scholar
  44. 44.
    Tellez CS, Juri DE, Do K, Bernauer AM, Thomas CL, Damiani LA, et al. EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. Cancer Res. 2011;71(8):3087–97.CrossRefGoogle Scholar
  45. 45.
    Li A, Omura N, Hong SM, Vincent A, Walter K, Griffith M, et al. Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. Cancer Res. 2010;70(13):5226–37.CrossRefGoogle Scholar
  46. 46.
    Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004;432(7015):332–7.CrossRefGoogle Scholar
  47. 47.
    Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008;68(3):918–26.CrossRefGoogle Scholar
  48. 48.
    Grugan KD, Miller CG, Yao Y, Michaylira CZ, Ohashi S, Klein-Szanto AJ, et al. Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion. Proc Natl Acad Sci U S A. 2010;107(24):11026–31.CrossRefGoogle Scholar
  49. 49.
    Yashiro M, Hirakawa K. Cancer-stromal interactions in scirrhous gastric carcinoma. Cancer Microenviron. 2010;3(1):127–35.CrossRefGoogle Scholar
  50. 50.
    Fuyuhiro Y, Yashiro M, Noda S, Matsuoka J, Hasegawa T, Kato Y, et al. Cancer-associated orthotopic myofibroblasts stimulates the motility of gastric carcinoma cells. Cancer Sci. 2012;103(4):797–805.CrossRefGoogle Scholar
  51. 51.
    Kurashige J, Mima K, Sawada G, Takahashi Y, Eguchi H, Sugimachi K, et al. Epigenetic modulation and repression of miR-200b by cancer-associated fibroblasts contribute to cancer invasion and peritoneal dissemination in gastric cancer. Carcinogenesis. 2015;36(1):133–41.CrossRefGoogle Scholar
  52. 52.
    Yanaka Y, Muramatsu T, Uetake H, Kozaki K, Inazawa J. miR-544a induces epithelial-mesenchymal transition through the activation of WNT signaling pathway in gastric cancer. Carcinogenesis. 2015;36(11):1363–71.CrossRefGoogle Scholar
  53. 53.
    Harazono Y, Muramatsu T, Endo H, Uzawa N, Kawano T, Harada K, et al. miR-655 is an EMT-suppressive microRNA targeting ZEB1 and TGFBR2. PLoS One. 2013;8(5):e62757.CrossRefGoogle Scholar
  54. 54.
    Yamamoto S, Inoue J, Kawano T, Kozaki K, Omura K, Inazawa J. The impact of miRNA-based molecular diagnostics and treatment of NRF2-stabilized tumors. Mol Cancer Res. 2014;12(1):58–68.CrossRefGoogle Scholar
  55. 55.
    Uesugi A, Kozaki K, Tsuruta T, Furuta M, Morita K, Imoto I, et al. The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. Cancer Res. 2011;71(17):5765–78.CrossRefGoogle Scholar
  56. 56.
    Tsuruta T, Kozaki K, Uesugi A, Furuta M, Hirasawa A, Imoto I, et al. miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer. Cancer Res. 2011;71(20):6450–62.CrossRefGoogle Scholar
  57. 57.
    Roberts DD. Regulation of tumor growth and metastasis by thrombospondin-1. FASEB J. 1996;10(10):1183–91.CrossRefGoogle Scholar
  58. 58.
    Raugi GJ, Olerud JE, Gown AM. Thrombospondin in early human wound tissue. J Invest Dermatol. 1987;89(6):551–4.CrossRefGoogle Scholar
  59. 59.
    Kashihara H, Shimada M, Yoshikawa K, Higashijima J, Tokunaga T, Nishi M, et al. Correlation between thrombospondin-1 expression in non-cancer tissue and gastric carcinogenesis. Anticancer Res. 2017;37(7):3547–52.PubMedGoogle Scholar
  60. 60.
    Eckmann L, Nebelsiek T, Fingerle AA, Dann SM, Mages J, Lang R, et al. Opposing functions of IKKbeta during acute and chronic intestinal inflammation. Proc Natl Acad Sci U S A. 2008;105(39):15058–63.CrossRefGoogle Scholar
  61. 61.
    Alvarez MC, Ladeira MS, Scaletsky IC, Pedrazzoli J Jr, Ribeiro ML. Methylation pattern of THBS1, GATA-4, and HIC1 in pediatric and adult patients infected with Helicobacter pylori. Dig Dis Sci. 2013;58(10):2850–7.CrossRefGoogle Scholar
  62. 62.
    Mazurek S, Boschek CB, Hugo F, Eigenbrodt E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol. 2005;15(4):300–8.CrossRefGoogle Scholar
  63. 63.
    Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452(7184):230–3.CrossRefGoogle Scholar
  64. 64.
    Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature. 2008;452(7184):181–6.CrossRefGoogle Scholar
  65. 65.
    Mazurek S. Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol. 2011;43(7):969–80.CrossRefGoogle Scholar
  66. 66.
    Noguchi T, Yamada K, Inoue H, Matsuda T, Tanaka T. The L- and R-type isozymes of rat pyruvate kinase are produced from a single gene by use of different promoters. J Biol Chem. 1987;262(29):14366–71.PubMedGoogle Scholar
  67. 67.
    Clower CV, Chatterjee D, Wang Z, Cantley LC, Vander Heiden MG, Krainer AR. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci U S A. 2010;107(5):1894–9.CrossRefGoogle Scholar
  68. 68.
    Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.CrossRefGoogle Scholar
  69. 69.
    Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008;18(1):54–61.CrossRefGoogle Scholar
  70. 70.
    Tong X, Zhao F, Thompson CB. The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr Opin Genet Dev. 2009;19(1):32–7.CrossRefGoogle Scholar
  71. 71.
    Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14.CrossRefGoogle Scholar
  72. 72.
    Shiroki T, Yokoyama M, Tanuma N, Maejima R, Tamai K, Yamaguchi K, et al. Enhanced expression of the M2 isoform of pyruvate kinase is involved in gastric cancer development by regulating cancer-specific metabolism. Cancer Sci. 2017;108(5):931–40.CrossRefGoogle Scholar
  73. 73.
    Lim JY, Yoon SO, Seol SY, Hong SW, Kim JW, Choi SH, et al. Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer. World J Gastroenterol. 2012;18(30):4037–43.CrossRefGoogle Scholar
  74. 74.
    Kwon OH, Kang TW, Kim JH, Kim M, Noh SM, Song KS, et al. Pyruvate kinase M2 promotes the growth of gastric cancer cells via regulation of Bcl-xL expression at transcriptional level. Biochem Biophys Res Commun. 2012;423(1):38–44.CrossRefGoogle Scholar
  75. 75.
    Wang LY, Liu YP, Chen LG, Chen YL, Tan L, Liu JJ, et al. Pyruvate kinase M2 plays a dual role on regulation of the EGF/EGFR signaling via E-cadherin-dependent manner in gastric cancer cells. PLoS One. 2013;8(6):e67542.CrossRefGoogle Scholar
  76. 76.
    Sutherland LC, Wang K, Robinson AG. RBM5 as a putative tumor suppressor gene for lung cancer. J Thorac Oncol. 2010;5(3):294–8.CrossRefGoogle Scholar
  77. 77.
    Maarabouni MM, Williams GT. The antiapoptotic RBM5/LUCA-15/H37 gene and its role in apoptosis and human cancer: research update. Sci World J. 2006;6:1705–12.CrossRefGoogle Scholar
  78. 78.
    Sutherland LC, Rintala-Maki ND, White RD, Morin CD. RNA binding motif (RBM) proteins: a novel family of apoptosis modulators? J Cell Biochem. 2005;94(1):5–24.CrossRefGoogle Scholar
  79. 79.
    Bechara EG, Sebestyen E, Bernardis I, Eyras E, Valcarcel J. RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation. Mol Cell. 2013;52(5):720–33.CrossRefGoogle Scholar
  80. 80.
    Fushimi K, Ray P, Kar A, Wang L, Sutherland LC, Wu JY. Up-regulation of the proapoptotic caspase 2 splicing isoform by a candidate tumor suppressor, RBM5. Proc Natl Acad Sci U S A. 2008;105(41):15708–13.CrossRefGoogle Scholar
  81. 81.
    Bonnal S, Martinez C, Forch P, Bachi A, Wilm M, Valcarcel J. RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition. Mol Cell. 2008;32(1):81–95.CrossRefGoogle Scholar
  82. 82.
    Kobayashi T, Ishida J, Musashi M, Ota S, Yoshida T, Shimizu Y, et al. p53 transactivation is involved in the antiproliferative activity of the putative tumor suppressor RBM5. Int J Cancer. 2011;128(2):304–18.CrossRefGoogle Scholar
  83. 83.
    Liang H, Zhang J, Shao C, Zhao L, Xu W, Sutherland LC, et al. Differential expression of RBM5, EGFR and KRAS mRNA and protein in non-small cell lung cancer tissues. J Exp Clin Cancer Res. 2012;31:36.CrossRefGoogle Scholar
  84. 84.
    Oh JJ, West AR, Fishbein MC, Slamon DJ. A candidate tumor suppressor gene, H37, from the human lung cancer tumor suppressor locus 3p21.3. Cancer Res. 2002;62(11):3207–13.PubMedGoogle Scholar
  85. 85.
    Kobayashi T, Ishida J, Shimizu Y, Kawakami H, Suda G, Muranaka T, et al. Decreased RNA-binding motif 5 expression is associated with tumor progression in gastric cancer. Tumour Biol. 2017;39(3):1010428317694547.CrossRefGoogle Scholar
  86. 86.
    Hirata K, Suzuki H, Imaeda H, Matsuzaki J, Tsugawa H, Nagano O, et al. CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence. Br J Cancer. 2013;109(2):379–86.CrossRefGoogle Scholar
  87. 87.
    Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65(23):10946–51.CrossRefGoogle Scholar
  88. 88.
    Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104(24):10158–63.CrossRefGoogle Scholar
  89. 89.
    Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(−) and thereby promotes tumor growth. Cancer Cell. 2011;19(3):387–400.CrossRefGoogle Scholar
  90. 90.
    Tsugawa H, Suzuki H, Saya H, Hatakeyama M, Hirayama T, Hirata K, et al. Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe. 2012;12(6):764–77.CrossRefGoogle Scholar
  91. 91.
    Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, et al. Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nat Commun. 2012;3:883.CrossRefGoogle Scholar
  92. 92.
    Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from burkitt's lymphoma. Lancet. 1964;1(7335):702–3.CrossRefGoogle Scholar
  93. 93.
    Jha HC, Banerjee S, Robertson ES. The role of gammaherpesviruses in cancer pathogenesis. Pathogens. 2016;5(1):E18.CrossRefGoogle Scholar
  94. 94.
    Le Negrate G. Viral interference with innate immunity by preventing NF-kappaB activity. Cell Microbiol. 2012;14(2):168–81.CrossRefGoogle Scholar
  95. 95.
    Shimizu T, Marusawa H, Endo Y, Chiba T. Inflammation-mediated genomic instability: roles of activation-induced cytidine deaminase in carcinogenesis. Cancer Sci. 2012;103(7):1201–6.CrossRefGoogle Scholar
  96. 96.
    Kawata S, Yashima K, Yamamoto S, Sasaki S, Takeda Y, Hayashi A, et al. AID, p53 and MLH1 expression in early gastric neoplasms and the correlation with the background mucosa. Oncol Lett. 2015;10(2):737–43.CrossRefGoogle Scholar
  97. 97.
    Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, et al. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med. 2007;13(4):470–6.CrossRefGoogle Scholar
  98. 98.
    Goto A, Hirahashi M, Osada M, Nakamura K, Yao T, Tsuneyoshi M, et al. Aberrant activation-induced cytidine deaminase expression is associated with mucosal intestinalization in the early stage of gastric cancer. Virchows Arch. 2011;458(6):717–24.CrossRefGoogle Scholar
  99. 99.
    Mohri T, Nagata K, Kuwamoto S, Matsushita M, Sugihara H, Kato M, et al. Aberrant expression of AID and AID activators of NF-kappaB and PAX5 is irrelevant to EBV-associated gastric cancers, but is associated with carcinogenesis in certain EBV-non-associated gastric cancers. Oncol Lett. 2017;13(6):4133–40.CrossRefGoogle Scholar
  100. 100.
    Shimizu T, Marusawa H, Matsumoto Y, Inuzuka T, Ikeda A, Fujii Y, et al. Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection. Gastroenterology. 2014;147(2):407–17 e3.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of BiochemistryKeio University School of MedicineShinjuku-kuJapan
  2. 2.Medical Education CenterKeio University School of Medicine, 35 ShinanomachiShinjuku-kuJapan

Personalised recommendations