Gene silencing of Nox4 by CpG island methylation during hepatocarcinogenesis in rats

The association between the downregulation of genes and DNA methylation in their CpG islands has been extensively studied as a mechanism that favors carcinogenesis. The objective of this study was to analyze the methylation of a set of genes selected based on their microarray expression profiles dur...

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Published in:Biology open 2017-01, Vol.6 (1), p.59-70
Main Authors: López-Álvarez, Guadalupe S, Wojdacz, Tomasz K, García-Cuellar, Claudia M, Monroy-Ramírez, Hugo C, Rodríguez-Segura, Miguel A, Pacheco-Rivera, Ruth A, Valencia-Antúnez, Carlos A, Cervantes-Anaya, Nancy, Soto-Reyes, Ernesto, Vásquez-Garzón, Verónica R, Sánchez-Pérez, Yesennia, Villa-Treviño, Saúl
Format: Article
Language:English
Subjects:
Carcinogenesis
Carcinogens
Casp3
Chemical hepatocarcinogenesis
Cldn1
CpG islands
Deoxyribonucleic acid
Deregulation
DNA
DNA methylation
DNA microarrays
Downregulation
Gene expression
Gene silencing
Genes
Islands
Liver
mRNA
NOX4 protein
Nox4, DNA methylation
Pex11a
Rats
Silence
Tumor suppressor genes
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Summary:The association between the downregulation of genes and DNA methylation in their CpG islands has been extensively studied as a mechanism that favors carcinogenesis. The objective of this study was to analyze the methylation of a set of genes selected based on their microarray expression profiles during the process of hepatocarcinogenesis. Rats were euthanized at: 24 h, 7, 11, 16 and 30 days and 5, 9, 12 and 18 months post-treatment. We evaluated the methylation status in the CpG islands of four deregulated genes (Casp3, Cldn1, Pex11a and Nox4) using methylation-sensitive high-resolution melting technology for the samples obtained from different stages of hepatocarcinogenesis. We did not observe methylation in Casp3, Cldn1 or Pex11a. However, Nox4 exhibited altered methylation patterns, reaching a maximum of 10%, even during the early stages of hepatocarcinogenesis. We observed downregulation of mRNA and protein of Nox4 (97.5% and 40%, respectively) after the first carcinogenic stimulus relative to the untreated samples. Our results suggest that Nox4 downregulation is associated with DNA methylation of the CpG island in its promoter. We propose that methylation is a mechanism that can silence the expression of Nox4, which could contribute to the acquisition of neoplastic characteristics during hepatocarcinogenesis in rats.
ISSN:2046-6390
2046-6390
DOI:10.1242/bio.020370