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Epigenetics in esophageal cancers

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Esophageal cancers are a challenging upper gastrointestinal tract tumor entity for interdisciplinary oncology. For the two main histotypes, namely esophageal squamous cell carcinomas and Barrett’s adenocarcinomas, several genetic aberrations have been shown to contribute to carcinogenesis and progression as well as to represent potential novel targets for therapeutic intervention. This is paralleled by growing insight into epigenetic alterations of esophageal cancers. Studies involving the analyses of human tissue specimens predominantly describe altered patterns of miRNA expression, DNA methylation patterns, and histone marks levels. This review provides a critical update on this increasing knowledge of epigenetic alteration in esophageal cancers by specifically focusing on the translational aspects of epigenetic analyses from human tissue specimens.

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  1. Akagi I, Miyashita M, Ishibashi O, Mishima T, Kikuchi K, Makino H, Nomura T, Hagiwara N, Uchida E, Takizawa T (2011) Relationship between altered expression levels of MIR21, MIR143, MIR145, and MIR205 and clinicopathologic features of esophageal squamous cell carcinoma. Dis Esophagus 24:523–530

  2. Alvarez H, Opalinska J, Zhou L, Sohal D, Fazzari MJ, Yu Y, Montagna C, Montgomery EA, Canto M, Dunbar KB, Wang J, Roa JC, Mo Y, Bhagat T, Ramesh KH, Cannizzaro L, Mollenhauer J, Thompson RF, Suzuki M, Meltzer SJ, Melnick A, Greally JM, Maitra A, Verma A (2011) Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis. PLoS Genet 7:e1001356

  3. Baba Y, Watanabe M, Baba H (2013) A review of the alterations in DNA methylation in esophageal squamous cell carcinoma. Surg Today 43:1355–1364

  4. Bolden JE, Shi W, Jankowski K, Kan CY, Cluse L, Martin BP, MacKenzie KL, Smyth GK, Johnstone RW (2013) HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses. Cell Death Dis 4:e519

  5. Chen J, Kwong DL, Cao T, Hu Q, Zhang L, Ming X, Chen J, Fu L, Guan X (2013) Esophageal squamous cell carcinoma (ESCC): advance in genomics and molecular genetics. Dis Esophagus (in press)

  6. Christman JK (2002) 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 21:5483–5495

  7. Cook MB, Chow WH, Devesa SS (2009) Oesophageal cancer incidence in the United States by race, sex, and histologic type, 1977–2005. Br J Cancer 101:855–859

  8. Fan H, Liu D, Qiu X, Qiao F, Wu Q, Su X, Zhang F, Song Y, Zhao Z, Xie W (2010) A functional polymorphism in the DNA methyltransferase-3A promoter modifies the susceptibility in gastric cancer but not in esophageal carcinoma. BMC Med 8:12

  9. Fanelli M, Amatori S, Barozzi I, Soncini M, Dal Zuffo R, Bucci G, Capra M, Quarto M, Dellino GI, Mercurio C, Alcalay M, Viale G, Pelicci PG, Minucci S (2010) Pathology tissue-chromatin immunoprecipitation, coupled with high-throughput sequencing, allows the epigenetic profiling of patient samples. Proc Natl Acad Sci U S A 107:21535–21540

  10. Feber A, Xi L, Luketich JD, Pennathur A, Landreneau RJ, Wu M, Swanson SJ, Godfrey TE, Litle VR (2008) MicroRNA expression profiles of esophageal cancer. J Thorac Cardiovasc Surg 135:255–260

  11. Garman KS, Owzar K, Hauser ER, Westfall K, Anderson BR, Souza RF, Diehl AM, Provenzale D, Shaheen NJ (2013) MicroRNA expression differentiates squamous epithelium from Barrett’s esophagus and esophageal cancer. Dig Dis Sci 58:3178–3188

  12. Guo M, House MG, Suzuki H, Ye Y, Brock MV, Lu F, Liu Z, Rustgi AK, Herman JG (2007) Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer. Int J Cancer 121:1219–1226

  13. Hamano R, Miyata H, Yamasaki M, Kurokawa Y, Hara J, Moon JH, Nakajima K, Takiguchi S, Fujiwara Y, Mori M, Doki Y (2011) Overexpression of miR-200c induces chemoresistance in esophageal cancers mediated through activation of the Akt signaling pathway. Clin Cancer Res 17:3029–3038

  14. Hoshino I, Matsubara H, Hanari N, Mori M, Nishimori T, Yoneyama Y, Akutsu Y, Sakata H, Matsushita K, Seki N, Ochiai T (2005) Histone deacetylase inhibitor FK228 activates tumor suppressor Prdx1 with apoptosis induction in esophageal cancer cells. Clin Cancer Res 11:7945–7952

  15. I H, Ko E, Kim Y, Cho EY, Han J, Park J, Kim K, Kim DH, Shim YM (2010) Association of global levels of histone modifications with recurrence-free survival in stage IIB and III esophageal squamous cell carcinomas. Cancer Epidemiol Biomark Prev 19:566–573

  16. Iwagami S, Baba Y, Watanabe M, Shigaki H, Miyake K, Ishimoto T, Iwatsuki M, Sakamaki K, Ohashi Y, Baba H (2013) LINE-1 hypomethylation is associated with a poor prognosis among patients with curatively resected esophageal squamous cell carcinoma. Ann Surg 257:449–455

  17. Kassis ES, Zhao M, Hong JA, Chen GA, Nguyen DM, Schrump DS (2006) Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells. J Thorac Cardiovasc Surg 131:298–306

  18. Kong KL, Kwong DL, Chan TH, Law SY, Chen L, Li Y, Qin YR, Guan XY (2012) MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor. Gut 61:33–42

  19. Langer R, Mutze K, Becker K, Feith M, Ott K, Hofler H, Keller G (2010) Expression of class I histone deacetylases (HDAC1 and HDAC2) in oesophageal adenocarcinomas: an immunohistochemical study. J Clin Pathol 63:994–998

  20. Leidner RS, Ravi L, Leahy P, Chen Y, Bednarchik B, Streppel M, Canto M, Wang JS, Maitra A, Willis J, Markowitz SD, Barnholtz-Sloan J, Adams MD, Chak A, Guda K (2012) The microRNAs, MiR-31 and MiR-375, as candidate markers in Barrett’s esophageal carcinogenesis. Genes Chromosomes Cancer 51:473–479

  21. Li X, Lin R, Li J (2011) Epigenetic silencing of microRNA-375 regulates PDK1 expression in esophageal cancer. Dig Dis Sci 56:2849–2856

  22. Lima SC, Hernandez-Vargas H, Simao T, Durand G, Kruel CD, Le Calvez-Kelm F, Ribeiro Pinto LF, Herceg Z (2011) Identification of a DNA methylome signature of esophageal squamous cell carcinoma and potential epigenetic biomarkers. Epigenetics 6:1217–1227

  23. Lin DC, Du XL, Wang MR (2009) Protein alterations in ESCC and clinical implications: a review. Dis Esophagus 22:9–20

  24. Lujambio A, Calin GA, Villanueva A, Ropero S, Sanchez-Cespedes M, Blanco D, Montuenga LM, Rossi S, Nicoloso MS, Faller WJ, Gallagher WM, Eccles SA, Croce CM, Esteller M (2008) A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci U S A 105:13556–13561

  25. Mathe EA, Nguyen GH, Bowman ED, Zhao Y, Budhu A, Schetter AJ, Braun R, Reimers M, Kumamoto K, Hughes D, Altorki NK, Casson AG, Liu CG, Wang XW, Yanaihara N, Hagiwara N, Dannenberg AJ, Miyashita M, Croce CM, Harris CC (2009) MicroRNA expression in squamous cell carcinoma and adenocarcinoma of the esophagus: associations with survival. Clin Cancer Res 15:6192–6200

  26. Mohammad HP, Baylin SB (2010) Linking cell signaling and the epigenetic machinery. Nat Biotechnol 28:1033–1038

  27. Murata A, Baba Y, Watanabe M, Shigaki H, Miyake K, Ishimoto T, Iwatsuki M, Iwagami S, Yoshida N, Oki E, Morita M, Nakao M, Baba H (2013) IGF2 DMR0 methylation, loss of imprinting, and patient prognosis in esophageal squamous cell carcinoma. Ann Surg Oncol 21:1166–1174

  28. Pennathur A, Gibson MK, Jobe BA, Luketich JD (2013) Oesophageal carcinoma. Lancet 381:400–412

  29. Shigaki H, Baba Y, Watanabe M, Iwagami S, Miyake K, Ishimoto T, Iwatsuki M, Baba H (2012) LINE-1 hypomethylation in noncancerous esophageal mucosae is associated with smoking history. Ann Surg Oncol 19:4238–4243

  30. Suzuki H, Maruyama R, Yamamoto E, Kai M (2013) Epigenetic alteration and microRNA dysregulation in cancer. Front Genet 4:258

  31. Tili E, Michaille JJ, Croce CM (2013) MicroRNAs play a central role in molecular dysfunctions linking inflammation with cancer. Immunol Rev 253:167–184

  32. Toh Y, Yamamoto M, Endo K, Ikeda Y, Baba H, Kohnoe S, Yonemasu H, Hachitanda Y, Okamura T, Sugimachi K (2003) Histone H4 acetylation and histone deacetylase 1 expression in esophageal squamous cell carcinoma. Oncol Rep 10:333–338

  33. Tzao C, Tung HJ, Jin JS, Sun GH, Hsu HS, Chen BH, Yu CP, Lee SC (2009) Prognostic significance of global histone modifications in resected squamous cell carcinoma of the esophagus. Mod Pathol 22:252–260

  34. Wang B, Yin BL, He B, Chen C, Zhao M, Zhang W, Xia ZK, Pan Y, Tang J, Zhou X, Yin N (2012) Overexpression of DNA damage-induced 45 alpha gene contributes to esophageal squamous cell cancer by promoter hypomethylation. J Exp Clin Cancer Res 31:11

  35. Wang N, Zhang CQ, He JH, Duan XF, Wang YY, Ji X, Zang WQ, Li M, Ma YY, Wang T, Zhao GQ (2013) MiR-21 down-regulation suppresses cell growth, invasion and induces cell apoptosis by targeting FASL, TIMP3, and RECK genes in esophageal carcinoma. Dig Dis Sci 58:1863–1870

  36. Wong NA, Wilding J, Bartlett S, Liu Y, Warren BF, Piris J, Maynard N, Marshall R, Bodmer WF (2005) CDX1 is an important molecular mediator of Barrett’s metaplasia. Proc Natl Acad Sci U S A 102:7565–7570

  37. Wu X, Ajani JA, Gu J, Chang DW, Tan W, Hildebrandt MA, Huang M, Wang KK, Hawk E (2013) MicroRNA expression signatures during malignant progression from Barrett’s esophagus to esophageal adenocarcinoma. Cancer Prev Res (Phila) 6:196–205

  38. Zhang HY, Spechler SJ, Souza RF (2009) Esophageal adenocarcinoma arising in Barrett esophagus. Cancer Lett 275:170–177

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Correspondence to Silke Lassmann.

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Ahrens, T.D., Werner, M. & Lassmann, S. Epigenetics in esophageal cancers. Cell Tissue Res 356, 643–655 (2014). https://doi.org/10.1007/s00441-014-1876-y

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  • Esophageal cancers
  • Epigenetics
  • miRNA
  • DNA Methylation
  • Histone marks