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Evaluation of epigenetic modulation of cyclooxygenase-2 as a prognostic marker for hepatocellular carcinoma

AuthorsFernández-Alvarez, Ana Julia ; Llorente-Izquierdo, Cristina ; Mayoral, Rafael ; Agra, Noelia ; Boscá, Lisardo ; Casado, Marta ; Martín-Sanz, Paloma
Issue Date2012
PublisherNature Publishing Group
CitationOncogenesis 1: e23 (2012)
AbstractCyclooxygenases (COX-1 and 2) catalyze the first step in prostanoid biosynthesis. They are implicated in homeostatic processes with an important role in inflammation and carcinogenesis. In the liver, COX-2 expression is restricted to proliferation or dedifferentiation situations. The COX-2 promoter contains numerous CpG islands that, when hypermethylated, result in transcriptionally silencing thus regulating the growth of carcinoma cells. In this work, we investigated whether a correlation exists between COX-2 expression and methylation signatures at the 5′region of the gene in hepatoma cell lines and human hepatocellular carcinoma (HCC). We also examined the acetylation status of the COX-2 promoter and the effects of histone deacetylase (HDAC) inhibitors on COX-2 expression. Our results suggest a significant association between reduced COX-2 expression and promoter hypermethylation of COX-2 and histone deacetylation in some hepatoma cell lines and in HCC. Treatment with demethylating agents or HDAC inhibitors restored the expression of COX-2. Moreover, in an HCC cohort, a statistically significant inverse association was observed between COX-2 mRNA levels and promoter methylation. In agreement with these data, a reduction of overall survival of the patients was observed after decreased COX-2 expression by promoter hypermethylation and histone H3 hypoacetylation.
DescriptionThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivative Works 3.0 Unported License.
Publisher version (URL)http://dx.doi.org/10.1038/oncsis.2012.23
Identifiersdoi: 10.1038/oncsis.2012.23
issn: 2157-9024
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