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Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett’s adenocarcinoma
  1. I Tischoff1,*,
  2. U R Hengge2,*,
  3. M Vieth3,
  4. C Ell4,
  5. M Stolte3,
  6. A Weber5,
  7. W E Schmidt6,
  8. A Tannapfel1
  1. 1Institute of Pathology, University of Bochum, Bochum, Germany
  2. 2Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany
  3. 3Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
  4. 4Clinic of Internal Medicine II, HSK-Clinics Wiesbaden, Wiesbaden, Germany
  5. 5Clinic of ENT Surgery, University of Leipzig, Leipzig, Germany
  6. 6Department of Internal Medicine I, St Josef Hospital, University of Bochum, Bochum, Germany
  1. Correspondence to:
    Professor Andrea Tannapfel
    Institute of Pathology, University of Bochum, Bürkle-de-la-Camp Platz 1, D-44789 Bochum, Germany; andrea.tannapfel{at}rub.de

Abstract

Background: The suppressors of cytokine signalling (SOCS) are inhibitors of cytokine signalling; methylation of SOCS-3 has been implicated in the tumorigenesis of liver as well as head and neck cancer.

Aims: This study was performed to elucidate the role of SOCS-1 and SOCS-3 in Barrett’s adenocarcinoma and its precursor lesions.

Methods: DNA of specimens from 19 Barrett’s adenocarcinomas, 56 Barrett’s intraepithelial neoplasias (n = 29 low grade and n = 27 high grade), 30 Barrett’s mucosa without neoplasia, 20 samples of normal squamous and gastric epithelium and four cell lines were studied using methylation specific PCR for the SOCS-1 and SOCS-3 promoter following microdissection. The presence of SOCS-3 mRNA transcripts was confirmed by semiquantitative real time PCR, and the SOCS-3 protein was analysed immunohistochemically.

Results: In normal squamous epithelium and normal gastric mucosa, neither SOCS-3 nor SOCS-1 methylation was observed. In Barrett’s mucosa without intraepithelial neoplasia, SOCS-3 methylation occurred in 4/30 cases (13%) whereas SOCS-1 was unmethylated. A hypermethylated SOCS-3 promoter was found in 14/19 Barrett’s adenocarcinomas (74%) and in 20/29 high and 6/27 low grade intraepithelial neoplasias (69% and 22%, respectively). SOCS-1 promoter hypermethylation occurred in 8/19 adenocarcinomas (42%) and in 6/29 high grade and 1/27 low grade intraepithelial neoplasias (21% and 4%, respectively). Methylation of the SOCS-3 promoter correlated with downregulation of SOCS-3 transcripts and protein expression in these tumours and various cell lines. In the cell lines tested, SOCS-3 and SOCS-1 transcripts increased after treatment with the demethylation compound 5-aza-2-deoxycytidine.

Conclusions: These data indicate that promoter methylation and subsequent transcript downregulation of SOCS-3 transcripts and, to a much lesser extent, SOCS-1 are involved in the multistep carcinogenesis of Barrett’s adenocarcinoma.

  • 5-AZA-DC, 5-aza-2-deoxycytidine
  • HGIN, high grade intraepithelial
  • JAK, Janus kinase
  • LGIN, low grade intraepithelial neoplasia
  • MSP, methylation specific PCR
  • SOCS, suppressors of cytokine signalling
  • STATs, signal transducers and activators of transcription neoplasia

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Footnotes

  • * I Tischoff and U R Hengge contributed equally to this work.

  • Published Online First 21 March 2007

  • Competing interests: None.

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