title: MiR-204 silencing in intraepithelial to invasive cutaneous squamous cell carcinoma progression.
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.
authors.affiliation: Department of Dermatology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain. AToll@parcdesalutmar.cat.|Group of Inflammatory and Neoplastic Dermatological Diseases, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. AToll@parcdesalutmar.cat.
authors.forename: Agustí
authors.initials: A
authors.lastname: Toll
authors.affiliation: Cytogenetics Molecular Biology Laboratory, Department of Pathology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Salgado
authors.affiliation: Cytogenetics Molecular Biology Laboratory, Department of Pathology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Espinet
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Díaz-Lagares
authors.affiliation: Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Hernández-Ruiz
authors.affiliation: Group of Inflammatory and Neoplastic Dermatological Diseases, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Andrades
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Sandoval
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Department of Dermatology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.|Group of Inflammatory and Neoplastic Dermatological Diseases, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Ramón M
authors.initials: RM
authors.lastname: Pujol
authors.affiliation: Group of Inflammatory and Neoplastic Dermatological Diseases, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. mhernandez@imim.es.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Hernández-Muñoz
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D055623:Keratosis, Actinic / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011401:Promoter Regions, Genetic; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: C549404:MIRN204 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Actinic keratosis; Cutaneous squamous cell carcinoma; DNA methylation; MAPK; STAT3; Sun-induced keratinocyte intraepithelial neoplasia; miR-204