title: Evaluation of epigenetic modulation of cyclooxygenase-2 as a prognostic marker for hepatocellular carcinoma.
abstract: Cyclooxygenases (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.
authors.affiliation: Instituto de Biomedicina de Valencia, IBV-CSIC, Valencia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Fernández-Alvarez
authors.forename: C
authors.initials: C
authors.lastname: Llorente-Izquierdo
authors.forename: R
authors.initials: R
authors.lastname: Mayoral
authors.forename: N
authors.initials: N
authors.lastname: Agra
authors.forename: L
authors.initials: L
authors.lastname: Boscá
authors.forename: M
authors.initials: M
authors.lastname: Casado
authors.forename: P
authors.initials: P
authors.lastname: Martín-Sanz
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