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Cancer Causes & Control
Published in: Cancer Causes & Control 6/2012

01-06-2012 | Original paper

Hypomethylation of Alu repetitive elements in esophageal mucosa, and its potential contribution to the epigenetic field for cancerization

Authors: Yasunori Matsuda, Satoshi Yamashita, Yi-Chia Lee, Tohru Niwa, Takeichi Yoshida, Ken Gyobu, Hiroyasu Igaki, Ryoji Kushima, Shigeru Lee, Ming-Shiang Wu, Harushi Osugi, Shigefumi Suehiro, Toshikazu Ushijima

Published in: Cancer Causes & Control | Issue 6/2012

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Abstract

Background

Aberrant hypermethylation of specific genes is present in esophageal squamous cell carcinomas (ESCCs). Such hypermethylation is also present in normal-appearing esophageal mucosae of ESCC patients and is considered to contribute to the formation of a field for cancerization. On the other hand, the presence of global hypomethylation in ESCCs or in their background esophageal mucosae is unknown.

Method

We collected 184 samples of esophageal mucosae (95 normal mucosae from healthy subjects, and 89 non-cancerous background mucosae from ESCC patients) and 93 samples of ESCCs. Methylation levels of repetitive elements (Alu, LINE1) and cancer/testis antigen genes (NY-ESO-1, MAGE-C1) were measured by bisulfite pyrosequencing and quantitative methylation-specific PCR, respectively.

Results

Methylation levels of Alu, LINE1, NY-ESO-1, and MAGE-C1 were significantly lower in ESCCs than in their background and normal mucosae. Also, in the background mucosae, a significant decrease of the Alu methylation level compared with the normal mucosae was present. In ESCCs, methylation levels of the two repetitive elements and the two cancer/testis antigen genes were correlated with each other.

Conclusion

This is the first study to show the presence of global hypomethylation in ESCCs, and even in their non-cancerous background mucosae. Alu hypomethylation might reflect the severity of an epigenetic field for cancerization.
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Literature
1.
Shibata A, Matsuda T, Ajiki W, Sobue T (2008) Trend in incidence of adenocarcinoma of the esophagus in Japan, 1993–2001. Jpn J Clin Oncol 38:464–468PubMedCrossRef
2.
Lu CL, Lang HC, Luo JC, Liu CC, Lin HC, Chang FY, Lee SD (2009) Increasing trend of the incidence of esophageal squamous cell carcinoma, but not adenocarcinoma, in Taiwan. Cancer Causes Control 21:269–274PubMedCrossRef
3.
Hongo M, Nagasaki Y, Shoji T (2009) Epidemiology of esophageal cancer: orient to occident. Effects of chronology, geography and ethnicity. J Gastroenterol Hepatol 24:729–735PubMedCrossRef
4.
Pesko P, Rakic S, Milicevic M, Bulajic P, Gerzic Z (1994) Prevalence and clinicopathologic features of multiple squamous cell carcinoma of the esophagus. Cancer 73:2687–2690PubMedCrossRef
5.
Shimizu Y, Tukagoshi H, Fujita M, Hosokawa M, Kato M, Asaka M (2001) Metachronous squamous cell carcinoma of the esophagus arising after endoscopic mucosal resection. Gastrointest Endosc 54:190–194PubMedCrossRef
6.
Slaughter DP, Southwick HW, Smejkal W (1953) Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6:963–968PubMedCrossRef
7.
8.
Oka D, Yamashita S, Tomioka T, Nakanishi Y, Kato H, Kaminishi M, Ushijima T (2009) The presence of aberrant DNA methylation in noncancerous esophageal mucosae in association with smoking history: a target for risk diagnosis and prevention of esophageal cancers. Cancer 115:3412–3426PubMedCrossRef
9.
Lee YC, Wang HP, Wang CP, Ko JY, Lee JM, Chiu HM, Lin JT, Yamashita S, Oka D, Watanabe N et al (2011) Revisit of field cancerization in squamous cell carcinoma of upper aero digestive tract: better risk assessment with epigenetic markers. Cancer Prev Res 4:1982–1992CrossRef
10.
Xing EP, Nie Y, Song Y, Yang GY, Cai YC, Wang LD, Yang CS (1999) Mechanisms of inactivation of p14ARF, p15INK4b, and p16INK4a genes in human esophageal squamous cell carcinoma. Clin Cancer Res 5:2704–2713PubMed
11.
Si HX, Tsao SW, Lam KY, Srivastava G, Liu Y, Wong YC, Shen ZY, Cheung AL (2001) E-cadherin expression is commonly downregulated by CpG island hypermethylation in esophageal carcinoma cells. Cancer Lett 173:71–78PubMedCrossRef
12.
Tanaka H, Shimada Y, Harada H, Shinoda M, Hatooka S, Imamura M, Ishizaki K (1998) Methylation of the 5′ CpG island of the FHIT gene is closely associated with transcriptional inactivation in esophageal squamous cell carcinomas. Cancer Res 58:3429–3434PubMed
13.
Wong ML, Tao Q, Fu L, Wong KY, Qiu GH, Law FB, Tin PC, Cheung WL, Lee PY, Tang JC et al (2006) Aberrant promoter hypermethylation and silencing of the critical 3p21 tumour suppressor gene, RASSF1A, in Chinese oesophageal squamous cell carcinoma. Int J Oncol 28:767–773PubMed
14.
Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89–92PubMedCrossRef
15.
16.
17.
De Smet C, De Backer O, Faraoni I, Lurquin C, Brasseur F, Boon T (1996) The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc Natl Acad Sci USA 93:7149–7153PubMedCrossRef
18.
Kaneda A, Tsukamoto T, Takamura-Enya T, Watanabe N, Kaminishi M, Sugimura T, Tatematsu M, Ushijima T (2004) Frequent hypomethylation in multiple promoter CpG islands is associated with global hypomethylation, but not with frequent promoter hypermethylation. Cancer Sci 95:58–64PubMedCrossRef
19.
Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res 32:e38PubMedCrossRef
20.
Weisenberger DJ, Campan M, Long TI, Kim M, Woods C, Fiala E, Ehrlich M, Laird PW (2005) Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 33:6823–6836PubMedCrossRef
21.
Caballero OL, Chen YT (2009) Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci 100:2014–2021PubMedCrossRef
22.
Gnjatic S, Nishikawa H, Jungbluth AA, Gure AO, Ritter G, Jager E, Knuth A, Chen YT, Old LJ (2006) NY-ESO-1: review of an immunogenic tumor antigen. Adv Cancer Res 95:1–30PubMedCrossRef
23.
Nuber N, Curioni-Fontecedro A, Matter C, Soldini D, Tiercy JM, von Boehmer L, Moch H, Dummer R, Knuth A, van den Broek M (2010) Fine analysis of spontaneous MAGE-C1/CT7-specific immunity in melanoma patients. Proc Natl Acad Sci USA 107:15187–15192PubMedCrossRef
24.
Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R (1998) DNA hypomethylation leads to elevated mutation rates. Nature 395:89–93PubMedCrossRef
25.
Eden A, Gaudet F, Waghmare A, Jaenisch R (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300:455PubMedCrossRef
26.
Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H, Jaenisch R (2003) Induction of tumors in mice by genomic hypomethylation. Science 300:489–492PubMedCrossRef
27.
Kaneda A, Kaminishi M, Sugimura T, Ushijima T (2004) Decreased expression of the seven ARP2/3 complex genes in human gastric cancers. Cancer Lett 212:203–210PubMedCrossRef
28.
Yoshida T, Yamashita S, Takamura-Enya T, Niwa T, Ando T, Enomoto S, Maekita T, Nakazawa K, Tatematsu M, Ichinose M et al (2011) Alu and Satalpha hypomethylation in Helicobacter pylori-infected gastric mucosae. Int J Cancer 128:33–39PubMedCrossRef
29.
Wilson AS, Power BE, Molloy PL (2007) DNA hypomethylation and human diseases. Biochim Biophys Acta 1775:138–162PubMed
30.
Kim BH, Cho NY, Shin SH, Kwon HJ, Jang JJ, Kang GH (2009) CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma. Virchows Arch 455:343–351PubMedCrossRef
31.
Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Chan AT, Schernhammer ES, Giovannucci EL, Fuchs CS (2008) A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J Natl Cancer Inst 100:1734–1738PubMedCrossRef
32.
Dewannieux M, Esnault C, Heidmann T (2003) LINE-mediated retrotransposition of marked Alu sequences. Nat Genet 35:41–48PubMedCrossRef
33.
Belancio VP, Hedges DJ, Deininger P (2008) Mammalian non-LTR retrotransposons: for better or worse, in sickness and in health. Genome Res 18:343–358PubMedCrossRef
34.
Bourc’his D, Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431:96–99PubMedCrossRef
35.
Guo ZS, Hong JA, Irvine KR, Chen GA, Spiess PJ, Liu Y, Zeng G, Wunderlich JR, Nguyen DM, Restifo NP et al (2006) De novo induction of a cancer/testis antigen by 5-aza-2′-deoxycytidine augments adoptive immunotherapy in a murine tumor model. Cancer Res 66:1105–1113PubMedCrossRef
36.
Oi S, Natsume A, Ito M, Kondo Y, Shimato S, Maeda Y, Saito K, Wakabayashi T (2009) Synergistic induction of NY-ESO-1 antigen expression by a novel histone deacetylase inhibitor, valproic acid, with 5-aza-2′-deoxycytidine in glioma cells. J Neurooncol 92:15–22PubMedCrossRef
Metadata
Title
Hypomethylation of Alu repetitive elements in esophageal mucosa, and its potential contribution to the epigenetic field for cancerization
Authors
Yasunori Matsuda
Satoshi Yamashita
Yi-Chia Lee
Tohru Niwa
Takeichi Yoshida
Ken Gyobu
Hiroyasu Igaki
Ryoji Kushima
Shigeru Lee
Ming-Shiang Wu
Harushi Osugi
Shigefumi Suehiro
Toshikazu Ushijima
Publication date
01-06-2012
Publisher
Springer Netherlands
Published in
Cancer Causes & Control / Issue 6/2012
Print ISSN: 0957-5243
Electronic ISSN: 1573-7225
DOI
https://doi.org/10.1007/s10552-012-9955-4

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