MiR-204 silencing in intraepithelial to invasive cutaneous squamous cell carcinoma progression

Agustí Toll, Rocío Salgado, Blanca Espinet, Angel Díaz-Lagares, Eugenia Hernández-Ruiz, Evelyn Andrades, Juan Sandoval, Manel Esteller, Ramón M. Pujol, Inmaculada Hernández-Muñoz

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23 Citations (Scopus)

Abstract

© 2016 The Author(s). Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and frequently progresses from an actinic keratosis (AK), a sun-induced keratinocyte intraepithelial neoplasia (KIN). Epigenetic mechanisms involved in the phenomenon of progression from AK to cSCC remain to be elicited. Methods: Expression of microRNAs in sun-exposed skin, AK and cSCC was analysed by Agilent microarrays. DNA methylation of miR-204 promoter was determined by bisulphite treatment and pyrosequencing. Identification of miR-204 targets and pathways was accomplished in HaCat cells. Immunofluorescence and immunohistochemistry were used to analyze STAT3 activation and PTPN11 expression in human biopsies. Results: cSCCs display a marked downregulation of miR-204 expression when compared to AK. DNA methylation of miR-204 promoter was identified as one of the repressive mechanisms that accounts for miR-204 silencing in cSCC. In HaCaT cells miR-204 inhibits STAT3 and favours the MAPK signaling pathway, likely acting through PTPN11, a nuclear tyrosine phosphatase that is a direct miR-204 target. In non-peritumoral AK lesions, activated STAT3, as detected by pY705-STAT3 immunofluorescence, is retained in the membrane and cytoplasm compartments, whereas AK lesions adjacent to cSCCs display activated STAT3 in the nuclei. Conclusions: Our data suggest that miR-204 may act as a "rheostat" that controls the signalling towards the MAPK pathway or the STAT3 pathway in the progression from AK to cSCC.
Original languageEnglish
Article number53
Pages (from-to)1
JournalMolecular Cancer
Volume15
Issue number1
DOIs
Publication statusPublished - 25 Jul 2016

Keywords

  • Actinic keratosis
  • Cutaneous squamous cell carcinoma
  • DNA methylation
  • MAPK
  • MiR-204
  • STAT3
  • Sun-induced keratinocyte intraepithelial neoplasia

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