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Integrin αV is a prognostic marker for cutaneous squamous cell carcinoma relapse

ABSTRACT: Early cutaneous squamous cell carcinomas (cSCCs) show epithelial differentiation features and good prognosis, whereas advanced cSCCs present mesenchymal traits and are associated with tumor relapse, metastasis, and poor survival. Prognostic biomarkers for cSCC relapse must therefore be found that accurately predict the clinical course of the disease, since established markers are suboptimal. Using mouse models of cSCC progression, we showed that the emergence of epithelial plastic cancer cells with a hybrid epithelial/mesenchymal phenotype promotes tumor progression to a mesenchymal state. These cells can be identified early on by the expression of integrin αV (ITGAV). Analysis of ITGAV expression in a cohort of primary cSCCs from patients provided prognostic information about the risk of relapse beyond current histopathological parameters. Together, our findings provide an opportunity to clinically implement ITGAV by standard immunodetection approaches and thereby improve patient stratification and therapeutic management.

ORGANISM(S): Mus musculus

PROVIDER: GSE233382 | GEO | 2024/08/08

REPOSITORIES: GEO

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Project description:Skin carcinogenesis is known to be a multi-step process with several stages along its malignant evolution. We hypothesized that transformation of normal epidermis to cutaneous squamous cell carcinoma (cSCC) is causally linked to alterations in miRNA expression. For this end we decided to evaluate their alterations in the pathologic states ending in cSCC. Total RNA was extracted from FFPE biopsies of five stages along the malignant evolution of keratinocytes towards cSCC: Normal epidermis, severe solar elastosis (SE), actinic keratosis (KIN1-2), advanced actinic keratosis, (KIN3) and well differentiated cSCC. Next generation small RNA sequencing was performed. We found that 18 miRNAs are over expressed and 28 miRNAs are under expressed in cSCC compared to normal epidermis. miR-424, miR-320, miR- 222 and miR-15a showed the highest fold change among the over expressed miRNAs. And miR-100, miR-101 and miR-497 showed the highest fold change among the under expressed miRNAs. Heat map of hierarchical clustering analysis of significantly changed miRNAs and principle component analysis disclosed that the most prominent change in miRNAs expression occurred in the switch from “early” stages; normal epidermis, solar elastosis and early actinic keratosis to the “late” stages of epidermal carcinogenesis; late actinic keratosis and cSCC. We found several miRNAs with "stage specific" alterations while others display a clear “gradual”, either progressive increase or decrease in expression along the malignant evolution of keratinocytes. The observed alterations focused in miRNAs involved in the regulation of AKT/mTOR or in those involved in epithelial to mesenchymal transition. We chose to concentrate on the evaluation of the molecular role of miR- 497. We found that it induces reversion of epithelial to mesenchymal transition. We proved that SERPINE-1 is its biochemical target. The present study allows us to further study the pathways which are regulated by miRNAs along the malignant evolution of keratinocytes towards cSCC.

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Integrin αV is a prognostic marker for cutaneous squamous cell carcinoma relapse

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