MiR-204 silencing in intraepithelial to invasive cutaneous squamous cell carcinoma progression
Toll Abelló, Agustí (Institut Hospital del Mar d'Investigacions Mèdiques)
Salgado Sánchez, Rocío Nieves (Hospital del Mar (Barcelona, Catalunya))
Espinet, Blanca (Hospital del Mar (Barcelona, Catalunya))
Diaz-Lagares, Angel (Institut d'Investigació Biomèdica de Bellvitge)
Hernández-Ruiz, Eugenia (Hospital Universitari Vall d'Hebron)
Andrades, Evelyn (Institut Hospital del Mar d'Investigacions Mèdiques)
Sandoval, Juan (Institut d'Investigació Biomèdica de Bellvitge)
Esteller, M. (Institució Catalana de Recerca i Estudis Avançats)
Pujol, Ramón M.. (Hospital del Mar (Barcelona, Catalunya))
Hernández-Muñoz, Inmaculada (Institut Hospital del Mar d'Investigacions Mèdiques)
Universitat Autònoma de Barcelona

Date:	2016
Abstract:	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. 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. 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. 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. The online version of this article (doi:10. 1186/s12943-016-0537-z) contains supplementary material, which is available to authorized users.
Grants:	Instituto de Salud Carlos III PI15-00236 Instituto de Salud Carlos III PI041728 Instituto de Salud Carlos III PI10-00785 Instituto de Salud Carlos III PI11-02070 Instituto de Salud Carlos III FEDER/RD09-0076-00036 Instituto de Salud Carlos III FEDER/RD06-0020-0040 Instituto de Salud Carlos III PS09-00973 Ministerio de Economía y Competitividad SAF2010-16089 Instituto de Salud Carlos III CM14-00067
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	MiR-204 ; Cutaneous squamous cell carcinoma ; Actinic keratosis ; Sun-induced keratinocyte intraepithelial neoplasia ; DNA methylation ; MAPK ; STAT3
Published in:	Molecular cancer, Vol. 15 (july 2016) , ISSN 1476-4598

DOI: 10.1186/s12943-016-0537-z
PMID: 27457246

15 p, 2.0 MB

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