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Mol Cancer. 2016 Jul 25;15(1):53. doi: 10.1186/s12943-016-0537-z.

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

Author information

1
Department of Dermatology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain. AToll@parcdesalutmar.cat.
2
Group of Inflammatory and Neoplastic Dermatological Diseases, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. AToll@parcdesalutmar.cat.
3
Cytogenetics Molecular Biology Laboratory, Department of Pathology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.
4
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
5
Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
6
Group of Inflammatory and Neoplastic Dermatological Diseases, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
7
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
8
Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain.
9
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
10
Department of Dermatology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.
11
Group of Inflammatory and Neoplastic Dermatological Diseases, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. mhernandez@imim.es.

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.

KEYWORDS:

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

PMID:
27457246
PMCID:
PMC4960761
DOI:
10.1186/s12943-016-0537-z
[Indexed for MEDLINE]
Free PMC Article

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