Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett's adenocarcinoma
Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett's adenocarcinoma
复制标题
DOI：
10.1136/gut.2006.111633
复制
发表时间：
2007-08-01
期刊：
影响因子：
24.5
通讯作者：
Tannapfel, A.
中科院分区：
文献类型：
--
作者：
Tischoff, I.;HEngge, U. R.;Tannapfel, A.
背景资料：细胞因子信号传导抑制因子（SOCS）是细胞因子信号传导的抑制因子; SOCS-3的甲基化与肝癌以及头颈癌的发生有关。目的：本研究旨在阐明SOCS-1和SOCS-3在Barrett腺癌及其前体病变中的作用。19例Barrett腺癌和56例Barrett上皮内瘤变标本的DNA（n = 29例低度和n = 27例高度），30例Barrett粘膜无瘤形成，采用甲基化特异性PCR技术，对20例正常鳞状上皮和胃上皮以及4种细胞系进行了SOCS-1和SOCS-3启动子甲基化特异性PCR研究。结果：在正常胃粘膜和鳞状上皮中，SOCS-3和SOCS-1均未发生甲基化。在没有上皮内瘤变的Barrett粘膜中，SOCS-3甲基化发生在4/30例（13%）中，而SOCS-1未甲基化。在14/19例Barrett腺癌（74%）和20/29例高级别上皮内瘤变和6/27例低级别上皮内瘤变（分别为69%和22%）中发现了高甲基化SOCS-3启动子。SOCS-1启动子甲基化发生在8/19例腺癌（42%）和6/29例高级别和1/27例低级别上皮内瘤变（分别为21%和4%）。SOCS-3启动子的甲基化与这些肿瘤和各种细胞系中SOCS-3转录本和蛋白表达的下调相关。在测试的细胞系中，SOCS-3和SOCS-1的成绩单增加治疗后与去甲基化化合物5-aza-2-deoxycytidine.Conclusions：这些数据表明，启动子甲基化和随后的转录下调SOCS-3的成绩单，并在较小的程度上，SOCS-1参与了多步骤癌变的巴雷特腺癌。
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.