Ali IU, Luke BT, Dean M, Greenwald P.. Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma. Br J Cancer 93: 953-959

Division for Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., Bethesda, MD 20892, USA.
British Journal of Cancer (Impact Factor: 4.84). 11/2005; 93(8):953-9. DOI: 10.1038/sj.bjc.6602806
Source: PubMed


Cyclooxygenase 2 (Cox-2) is upregulated in colorectal adenomas and carcinomas. Polymorphisms in the Cox-2 gene may influence its function and/or its expression and may modify the protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs), thereby impacting individuals' risk of developing colorectal cancer and response to prevention/intervention strategies. In a nested case-control study, four polymorphisms in the Cox-2 gene (two in the promoter, -663 insertion/deletion, GT/(GT) and -798 A/G; one in intron 5-5229, T/G; one in 3'untranslated region (UTR)-8494, T/C) were genotyped in 726 cases of colorectal adenomas and 729 age- and gender-matched controls in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. There was no significant association between the Cox-2 polymorphisms and adenoma development in the overall population. However, in males, the relatively rare heterozygous genotype GT/(GT) at -663 in the promoter and the variant homozygous genotype G/G at intron 5-5229 appeared to have inverse associations (odds ratio (OR)=0.59, confidence interval (CI): 0.34-1.02 and OR=0.48, CI: 0.24-0.99, respectively), whereas the heterozygous genotype T/C at 3'UTR-8494 had a positive association (OR=1.31, CI: 1.01-1.71) with adenoma development. Furthermore, the haplotype carrying the risk-conferring 3'UTR-8494 variant was associated with a 35% increase in the odds for adenoma incidence in males (OR=1.35, CI: 1.07-1.70), but the one with a risk allele at 3'UTR-8494 and a protective allele at intron 5-5229 had no effect on adenoma development (OR=0.85, CI: 0.66-1.09). Gender-related differences in adenoma risk were also noted with tobacco usage and protective effects of NSAIDs. Our analysis underscores the significance of the overall allelic architecture of Cox-2 as an important determinant for risk assessment.

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Available from: Brian Luke, Mar 18, 2014
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    • "examples of dysregulated miRNA expression have been shown to contribute to the pathogenesis most cancers (Croce 2009) and more recently, genetic polymorphisms in components of miRNA networks and their targets are being recognized as contributing factors in disease etiology (Ryan et al. 2010). Several studies have identified a common single nucleotide polymorphism (SNP) in the COX-2 gene at position 8473 (T8473C; rs5275) that is associated with increased risk and/or NSAID responsiveness in a number of cancers where COX-2 overexpression is a contributing factor(Ali et al. 2005; Campa et al. 2004; Ferguson et al. 2008; Gong et al. 2009; Langsenlehner et al. 2006; Ozhan et al. 2010; Shen et al. 2006; Siezen et al. 2005; Vogel et al. 2008). The T8473C SNP is located in exon 10 which encodes the COX-2 3′UTR suggesting a potential role in post-transcriptional regulation. "
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    ABSTRACT: The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in pathogenic states and a large amount of evidence has demonstrated constitutive COX-2 expression to be a contributing factor promoting colorectal cancer (CRC). Various genetic, epigenetic, and inflammatory pathways have been identified to be involved in the etiology and development of CRC. Alteration in these pathways can influence COX-2 expression at multiple stages of colon carcinogenesis allowing for elevated prostanoid biosynthesis to occur in the tumor microenvironment. In normal cells, COX-2 expression levels are potently regulated at the post-transcriptional level through various RNA sequence elements present within the mRNA 3' untranslated region (3'UTR). A conserved AU-rich element (ARE) functions to target COX-2 mRNA for rapid decay and translational inhibition through association with various RNA-binding proteins to influence the fate of COX-2 mRNA. Specific microRNAs (miRNAs) bind regions within the COX-2 3'UTR and control COX-2 expression. In this chapter, we discuss novel insights in the mechanisms of altered post-transcriptional regulation of COX-2 in CRC and how this knowledge may be used to develop novel strategies for cancer prevention and treatment.
    Full-text · Article · Aug 2012 · Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer
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    • "Many genetic variants within the COX-2 gene have been identified and select polymorphisms have shown disease association. Several studies have identified the variant allele of one particular single-nucleotide polymorphism (SNP), T8473C (rs5275), to be associated with increased risk and/or NSAID responsiveness in a number of cancers where COX-2 overexpression has been observed (Campa et al., 2004; Ali et al., 2005; Siezen et al., 2005; Langsenlehner et al., 2006; Shen et al., 2006; Ferguson et al., 2008; Vogel et al., 2008; Gong et al., 2009; Ozhan et al., 2010). The T8473C SNP is located in exon 10 which encodes the COX-2 3′-untranslated region (3′-UTR), and work from our group and others has identified the significance of this region in targeting COX-2 mRNA for posttranscriptional regulation (Young and Dixon, 2010). "
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    ABSTRACT: Elevated expression of the prostaglandin synthase cyclooxygenase-2 (COX-2) is commonly observed in many chronic inflammatory diseases and cancer. However, the mechanisms allowing for pathogenic COX-2 overexpression are largely unknown. The gene for COX-2 (PTGS2) carries a common single-nucleotide polymorphism (SNP) at position 8473 (T8473C), in exon 10 that is associated with diseases in which COX-2 overexpression is a contributing factor. We demonstrate that the T8473C SNP resides within a region that targets COX-2 mRNA for degradation through microRNA-mediated regulation. miR-542-3p was identified to bind transcripts derived from the 8473T allele and promote mRNA decay. By contrast, the presence of the variant 8473C allele interfered with miR-542-3p binding, allowing for mRNA stabilization, and this effect was rescued using a mutated miR-542-3p at the respective 8473 site. Colon cancer cells and tissue displayed COX-2 mRNA levels that were dependent on T8473C allele dosage, and allele-specific expression of COX-2 was observed to be a contributing factor promoting COX-2 overexpression. These findings provide a novel molecular explanation underlying disease susceptibility associated with COX-2 T8473C SNP, and identify it as a potential marker for identifying cancer patients best served through selective COX-2 inhibition.
    Full-text · Article · Aug 2011 · Oncogene
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    • "The only exception is a recent publication by Zhao et al. [49], which suggests an increased risk of esophageal squamous cancer associated to SNP rs20432 that is located in intron 5. This positive association, however, is not confirmed in other types of cancer [16,21,25,29,33,36,45]. "
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    ABSTRACT: Cyclooxygenase-2 (COX-2) is up-regulated in several types of cancer, and it is hypothesized that COX-2 expression may be genetically influenced. Here, we evaluate the association between single-nucleotide polymorphisms (SNPs) in the COX-2 gene (PTGS2) and the occurrence of breast cancer among Brazilian women. The study was conducted prospectively in two steps: First, we screened the promoter region and three fragments of the 3'-untranslated region of PTGS2 from 67 healthy Brazilians to identify SNPs and to select those with a minor allele frequency (MAF) of at least 0.10. The MAF of these selected SNPs was further characterized in 402 healthy volunteers to evaluate potential differences related to heterogeneous racial admixture and to estimate the existence of linkage disequilibrium among the SNPs. The second step was a case-control study with 318 patients and 273 controls designed to evaluate PTGS2 genotype- or haplotype-associated risk of breast cancer. The screening analysis indicated nine SNPs with the following MAFs: rs689465 (0.22), rs689466 (0.15), rs20415 (0.007), rs20417 (0.32), rs20419 (0.015), rs5270 (0.02), rs20424 (0.007), rs5275 (0.22) and rs4648298 (0.01). The SNPs rs689465, rs689466, rs20417 and rs5275 were further studied: Their genotypic distributions followed Hardy-Weinberg equilibrium and the MAFs were not affected by gender or skin color. Strong linkage disequilibrium was detected for rs689465, rs20417 and rs5275 in the three possible pairwise combinations. In the case-control study, there was a significant increase of rs5275TC heterozygotes in cases compared to controls (OR = 1.44, 95% CI = 1.01-2.06; P = 0.043), and the haplotype formed by rs689465G, rs689466A, rs20417G and rs5275C was only detected in cases. The apparent association with breast cancer was not confirmed for rs5275CC homozygotes or for the most frequent rs5275C-containing haplotypes. Our results indicate no strong association between the four most frequent PTGS2 SNPs and the risk of breast cancer.
    Full-text · Article · Nov 2010 · BMC Cancer
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