Promoter hypermethylation of cyclooxygenase-2 in gastric carcinoma.
Overexpression of cyclooxygenase-2 (COX-2) is associated with loss of apoptosis, enhancement of proliferation and tumorigenesis. The role of promoter methylation in the transcriptional silencing of cox-2 gene in human gastric cancer is less determined. We investigated 5 gastric cancer cell lines and 58 primary gastric carcinomas for the presence of promoter hypermethylation in cox-2 gene. Combined methylation-specific polymerase chain reaction analysis and bisulfite sequencing analysis revealed that the cox-2 promoter was methylated in 2 of the gastric cancer cell lines. Treatment with 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, induced COX-2 expression in the methylated gastric cancer cell line. Among the 58 primary gastric cancers, hypermethylation was detected in 25 (43.1%) cases. However, none of the normal gastric tissues showed methylation in cox-2. Promoter hypermethylation was associated with loss of protein expression as determined by immunostaining (p=0.005). Our results indicate that hypermethylation of the CpG island in the cox-2 gene is a major mechanism that mediates transcriptional silencing in a subset of gastric cancers. Thus, gastric cancers with methylation in cox-2 may not be good candidates for treatment with specific COX-2 inhibitors.
Yu
Jun
J
Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, PR China.
Leung
Wai K
WK
Lee
Tin-Lap
TL
Tse
Pete C H
PC
To
Ka Fai
KF
Sung
Joseph J Y
JJ
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D001483:Base Sequence; D051546:Cyclooxygenase 2; D019175:DNA Methylation; D017931:DNA Primers; D005260:Female; D005743:Gastrectomy; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases