RRC ID 42223
Author To KF, Chan MW, Leung WK, Ng EK, Yu J, Bai AH, Lo AW, Chu SH, Tong JH, Lo KW, Sung JJ, Chan FK.
Title Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line.
Journal Br J Cancer
Abstract The interleukin-mediated Janus kinase (JAK)/STAT pathway plays a crucial role in carcinogenesis. Recently, increased STAT3 activity was found in hepatocellular carcinoma and multiple myeloma in which there was silencing of SOCS-1 (suppressor of cytokine signalling-1) by gene promoter hypermethylation. We investigated the expression level of interleukin-6 (IL-6) and SOCS-1 in gastric cancer cell lines. Expression of SOCS-1 correlated with IL-6 level in most of the cell lines, except for AGS cells in which SOCS-1 was absent despite a high level of IL-6 production. Methylation analysis by methylation-specific polymerase chain reaction and bisulphite sequencing revealed that CpG island of SOCS-1 was densely methylated in AGS cells. Demethylation treatment by 5'aza-deoxycytidine restored SOCS-1 expression and also suppressed constitutive STAT3 phosphorylation in AGS cells. Moreover, methylation of SOCS-1 was detected in 27.5% (11 of 40) of primary gastric tumours samples, 10% (one of 10) of adjacent noncancer tissues but not in any (zero of nine) normal gastric mucosa. Methylation of SOCS-1 also correlated with the loss of mRNA expression in some primary gastric cancers. In conclusion, this is the first report to demonstrate that hypermethylation of SOCS-1 led to gene silencing in gastric cancer cell line and primary tumour samples. Downregulation of SOCS-1 cooperates with IL-6 in the activation of JAK/STAT pathway in gastric cancer.
Volume 91(7)
Pages 1335-41
Published 2004-10-4
DOI 10.1038/sj.bjc.6602133
PII 6602133
PMID 15354212
PMC PMC2409891
MeSH Carrier Proteins / biosynthesis Carrier Proteins / metabolism* Cell Transformation, Neoplastic DNA Methylation DNA-Binding Proteins / pharmacology* Down-Regulation Humans Interleukin-6 / pharmacology* Intracellular Signaling Peptides and Proteins* Janus Kinase 1 Protein-Tyrosine Kinases / pharmacology* RNA, Messenger / analysis RNA, Messenger / biosynthesis Repressor Proteins / biosynthesis Repressor Proteins / metabolism* Reverse Transcriptase Polymerase Chain Reaction STAT3 Transcription Factor Stomach Neoplasms / pathology* Suppressor of Cytokine Signaling 1 Protein Suppressor of Cytokine Signaling Proteins Trans-Activators / pharmacology* Tumor Cells, Cultured
IF 5.791
Times Cited 72
Human and Animal Cells MKN28(RCB1000) MKN45(RCB1001)