Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett’s adenocarcinoma

• Published in: Gut 2007-08, Vol.56 (8), p.1047-1053
• Main Authors: Tischoff, I, Hengge, U R, Vieth, M, Ell, C, Stolte, M, Weber, A, Schmidt, W E, Tannapfel, A
• Format: Article
• Language: English
• Subjects: 5-aza-2-deoxycytidine; 5-AZA-DC; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Apoptosis; Barrett Esophagus - genetics; Barrett Esophagus - metabolism; Barrett's Oesophagus; Biological and medical sciences; Carcinoma in Situ - genetics; Carcinoma, Squamous Cell - genetics; Cell Line, Tumor; Colleges & universities; CpG Islands - genetics; Cytokines; Deoxyribonucleic acid; Disease; DNA; DNA methylation; DNA, Neoplasm - genetics; Epigenetics; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophagus; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Head & neck cancer; HGIN; high grade intraepithelial; Humans; Inflammation; JAK; Janus kinase; Kinases; LGIN; Liver cancer; low grade intraepithelial neoplasia; Medical sciences; Methylation; methylation specific PCR; MSP; Neoplasm Proteins - genetics; Other diseases. Semiology; Promoter Regions, Genetic - genetics; Proteins; signal transducers and activators of transcription neoplasia; SOCS; STATs; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; suppressors of cytokine signalling; Transcription, Genetic - genetics; Tumors
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2006.111633

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.