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

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DOI

  • Guadalupe S López-Álvarez, Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV)
  • ,
  • Tomasz K Wojdacz
  • Claudia M García-Cuellar, Instituto Nacional de Cancerología (INCan)
  • ,
  • Hugo C Monroy-Ramírez, Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV)
  • ,
  • Miguel A Rodríguez Segura, Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV)
  • ,
  • Ruth A Pacheco Rivera, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas-IPN
  • ,
  • Carlos A Valencia-Antúnez, Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV)
  • ,
  • Nancy C Cervantes-Anaya, Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV)
  • ,
  • Ernesto Soto-Reyes, Instituto Nacional de Cancerología (INCan)
  • ,
  • Verónica R Vázquez-Garzón, Universidad Autónoma "Benito Juárez" de Oaxaca
  • ,
  • Yesennia Sánchez-Pérez, Instituto Nacional de Cancerología (INCan)
  • ,
  • Saúl Villa Treviño, Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV)

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 sacrificed at: 24 Hours, 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.

Original languageEnglish
JournalOpen Biology
Pages (from-to)59-70
Number of pages12
ISSN2046-2441
DOIs
Publication statusPublished - 2017

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