Toll Abelló, AgustíSalgado, RocíoEspinet Solà, BlancaDiaz-Lagares, AngelHernández Ruiz, EugeniaAndrades, EvelynSandoval, JuanEsteller, ManelPujol, Ramon M.Hernández Muñoz, Inmaculada2018-11-282018-11-282016-07-251476-4598https://hdl.handle.net/2445/126536Background: 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.application/pdfengcc-by (c) Toll, Agustí et al., 2016http://creativecommons.org/licenses/by/3.0/esEpigenèticaCàncer de pellCeratosiEpigeneticsSkin cancerKeratosisinfo:eu-repo/semantics/article6686602018-11-28info:eu-repo/semantics/openAccess27457246