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Aberrant methylation of the Cyclooxygenase 2 CpG island in colorectal tumors.
Cancer Res. 2000 Aug 01; 60(15):4044-8.CR

Abstract

Cyclooxygenases (COXs) are key enzymes that convert arachidonic acid to prostaglandins. Overexpression of one of the COX isozymes, COX2, has been shown to play an important role in colorectal cancer progression. Recently, however, low expression of COX2 has been reported in a subset of colorectal and gastric cancers. Aberrant CpG island methylation and associated transcriptional silencing are common in colorectal cancer, and we therefore investigated the potential role of methylation in the transcriptional silencing of COX2. We examined the methylation status of the COX2 5' CpG island in a series of tumor cell lines. Among the 33 cell lines examined, dense methylation (>70%) of COX2 was detected in 5 cell lines, and partial methylation was detected in 10 cell lines. Detailed methylation mapping using bisulfite genomic sequencing revealed that loss of expression of COX2 mRNA was closely correlated with methylation of a region upstream of exon 1, and expression could be restored by demethylation using the DNA methyltransferase inhibitor 5-aza-deoxycytidine. Aberrant methylation of COX2 was also detected in 12 of 92 (13%) unselected sporadic primary colorectal cancers and 7 of 50 (14%) colorectal adenomas. COX2 methylation was strongly associated with the presence of the CpG island methylator phenotype (P<0.01), inversely related to p53 gene mutation (P<0.01), and unrelated to microsatellite instability status. We propose that COX2 expression in colorectal tumors is modulated by functional factors that favor high expression and by the CpG island methylator phenotype that favors silencing in a subset of cases. These results raise the possibility that tumors with COX2 methylation may be less sensitive to treatment using specific COX2 inhibitors.

Authors+Show Affiliations

Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10945606

Citation

Toyota, M, et al. "Aberrant Methylation of the Cyclooxygenase 2 CpG Island in Colorectal Tumors." Cancer Research, vol. 60, no. 15, 2000, pp. 4044-8.
Toyota M, Shen L, Ohe-Toyota M, et al. Aberrant methylation of the Cyclooxygenase 2 CpG island in colorectal tumors. Cancer Res. 2000;60(15):4044-8.
Toyota, M., Shen, L., Ohe-Toyota, M., Hamilton, S. R., Sinicrope, F. A., & Issa, J. P. (2000). Aberrant methylation of the Cyclooxygenase 2 CpG island in colorectal tumors. Cancer Research, 60(15), 4044-8.
Toyota M, et al. Aberrant Methylation of the Cyclooxygenase 2 CpG Island in Colorectal Tumors. Cancer Res. 2000 Aug 1;60(15):4044-8. PubMed PMID: 10945606.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aberrant methylation of the Cyclooxygenase 2 CpG island in colorectal tumors. AU - Toyota,M, AU - Shen,L, AU - Ohe-Toyota,M, AU - Hamilton,S R, AU - Sinicrope,F A, AU - Issa,J P, PY - 2000/8/17/pubmed PY - 2000/9/2/medline PY - 2000/8/17/entrez SP - 4044 EP - 8 JF - Cancer research JO - Cancer Res VL - 60 IS - 15 N2 - Cyclooxygenases (COXs) are key enzymes that convert arachidonic acid to prostaglandins. Overexpression of one of the COX isozymes, COX2, has been shown to play an important role in colorectal cancer progression. Recently, however, low expression of COX2 has been reported in a subset of colorectal and gastric cancers. Aberrant CpG island methylation and associated transcriptional silencing are common in colorectal cancer, and we therefore investigated the potential role of methylation in the transcriptional silencing of COX2. We examined the methylation status of the COX2 5' CpG island in a series of tumor cell lines. Among the 33 cell lines examined, dense methylation (>70%) of COX2 was detected in 5 cell lines, and partial methylation was detected in 10 cell lines. Detailed methylation mapping using bisulfite genomic sequencing revealed that loss of expression of COX2 mRNA was closely correlated with methylation of a region upstream of exon 1, and expression could be restored by demethylation using the DNA methyltransferase inhibitor 5-aza-deoxycytidine. Aberrant methylation of COX2 was also detected in 12 of 92 (13%) unselected sporadic primary colorectal cancers and 7 of 50 (14%) colorectal adenomas. COX2 methylation was strongly associated with the presence of the CpG island methylator phenotype (P<0.01), inversely related to p53 gene mutation (P<0.01), and unrelated to microsatellite instability status. We propose that COX2 expression in colorectal tumors is modulated by functional factors that favor high expression and by the CpG island methylator phenotype that favors silencing in a subset of cases. These results raise the possibility that tumors with COX2 methylation may be less sensitive to treatment using specific COX2 inhibitors. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/10945606/Aberrant_methylation_of_the_Cyclooxygenase_2_CpG_island_in_colorectal_tumors_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=10945606 DB - PRIME DP - Unbound Medicine ER -