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Molecular Cancer
Published in: Molecular Cancer 1/2016

Open Access 01-12-2016 | Research

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

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

Published in: Molecular Cancer | Issue 1/2016

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Abstract

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.
Appendix
Available only for authorised users
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Metadata
Title
MiR-204 silencing in intraepithelial to invasive cutaneous squamous cell carcinoma progression
Authors
Agustí Toll
Rocío Salgado
Blanca Espinet
Angel Díaz-Lagares
Eugenia Hernández-Ruiz
Evelyn Andrades
Juan Sandoval
Manel Esteller
Ramón M Pujol
Inmaculada Hernández-Muñoz
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2016
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-016-0537-z

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