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

Abstract

BackgroundCutaneous 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.MethodsExpression 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.ResultscSCCs 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0537-z) contains supplementary material, which is available to authorized users.

The Polycomb proteins RING1B and EZH2 repress the tumoral pro-inflammatory function in metastasizing primary cutaneous squamous cell carcinoma

“…SCC13 cells were a generous gift from Dr. S. Aznar-Benitah (IRB, Barcelona, Spain) and cultured as previously described (8,9). Independent cell line characterization was performed in September 2017 by qGenomics (Barcelona, Spain) utilizing nine short tandem repeat (STR) loci (TH01, D21S11, D5S828, D13S317, D7S820, D16S539, CSF1PO, vWA and TPOX), a gender-specific marker (AMEL) to establish the presence of sex chromosomes, and a specific marker to detect the presence of murine sequences.…”

Low expression of microRNA-125b enhances the expression of STAT3 and contributes to cholesteatoma growth

“…STAT3 was found to have abnormally high expression in diseases with abnormal proliferation of keratinocytes; for instance, skin cancer and psoriasis [15,[28][29][30][31]. Several studies have shown that STAT3 is an important regulator of keratinocyte function, playing an important role in promoting proliferation as well as inhibiting differentiation and senescence of keratinocytes [32,33].…”

DNA Methylation in Epidermal Differentiation, Aging, and Cancer

“…Cancer-related genes found silenced in basal cell carcinoma are CDH13, SFN, TNFRSF10C, FHIT, SHH, APC, SFRP5, and RASSF1 (Brinkhuizen et al, 2012;Goldberg et al, 2006;Lodygin et al, 2003;Stamatelli et al, 2014;Takeuchi et al, 2002). Genes inactivated in cSCC are, for instance, the tumor suppressors CDKN2A, RB1, and CDH1 (Brown et al, 2004;Murao et al, 2006), and silencing of MIR204 appears to be involved in the progression from AK to cSCC (Toll et al, 2016).…”