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MicroRNA31 and MMP-1 contribute to the differentiated pathway of invasion -with enhanced epithelial-to-mesenchymal transition- in squamous cell carcinoma of the skin

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Abstract

Epithelial to mesenchymal transition (EMT) is an important mechanism of invasion in cutaneous squamous cell carcinomas (cSCCs) and has been found to be enhanced in tumors originated from actinic keratosis with transformation limited to the basal epithelial layer -differentiated pathway-, compared to cases with invasion subsequent to complete epidermal transformation -classical pathway-. Several microRNAs and proteins can contribute to EMT modulation in cSCCs. MicroRNA21 and microRNA31 are involved in posttranscriptional regulation of protein expression and could play a relevant role in EMT and cSCC progression. Throughout the EMT process upregulation of matrix metalloproteinases (MMPs) enhances invasiveness and MMP-1 and MMP-3 contribute to local invasion, angiogenesis and metastasis in cSCCs. Additionally, cSCC development is associated with PTEN loss and NF-κB, NOTCH-1 and p63 activation. The aim of this work is to identify differences in the expression of those molecules between both pathways of cSCCs development. Eight tissue microarrays from 80 consecutive cSCCs were analyzed using LNA-based miRNA in situ hybridization for miRNA21 and miRNA31 evaluation, and immunohistochemistry for MMP-1, MMP-3, PTEN, NOTCH-1, NF-κB, p63 and CD31. Significantly higher expression of miRNA31 (p < 0.0001) and MMP-1 (p = 0.0072) and angiogenesis (p = 0.0199) were found in the differentiated pathway, whereas PTEN loss (p = 0.0430) was more marked in the classical pathway. No significant differences were found for the other markers. Our findings support a contribution of miRNA31 and MMP-1 in the differentiated pathway, associated to EMT and increased microvascularization. The greater PTEN loss in the classical pathway indicate that its relevance in cSCC is not EMT-related.

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Acknowledgements

We acknowledge the excellent work of the Scientific and Technical Service of Immunohistochemistry, Lleida Institute for Biomedical Research Dr. Pifarré Foundation, IRBLleida, Hospital Universitari Arnau de Vilanova, Av. Alcalde Rovira Roure, 80, 25198, Lleida, Spain.

Funding

This research was funded by Leo Pharma.

Author information

Authors and Affiliations

  1. Department of Anatomic Pathology, Hospital Universitari General de Catalunya. Grupo QuirónSalud, Pedro i Pons, 1, 08195, Sant Cugat del Vallès, Spain

    M. T. Fernández-Figueras & E. Musulén

  2. Universitat Internacional de Catalunya, Carrer de Josep Trueta, Sant Cugat del Vallès, Spain

    M. T. Fernández-Figueras

  3. Department of Anatomic Pathology, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet, Badalona, Spain

    C. Carrato

  4. Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden

    X. Saenz-Sardà

  5. Josep Carreras Leukaemia Research Institute (IJC), Ctra de Can Ruti, Camí de les Escoles, 08916, Badalona, Spain

    E. Musulén

  6. Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet, Badalona, Spain

    M. J. Fuente

  7. Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    L. Puig

  8. Universitat Autònoma de Barcelona, Barcelona, Bellaterra, Spain

    L. Puig

Authors
  1. M. T. Fernández-Figueras
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  2. C. Carrato
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  3. X. Saenz-Sardà
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  4. E. Musulén
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  5. M. J. Fuente
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  6. L. Puig
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Corresponding author

Correspondence to M. T. Fernández-Figueras.

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Conflict of interest

MTFF has perceived consultancy/speaker’s honoraria from Almirall and funding for this research from Leo Pharma.

Ethics approval

Tissue use was approved by the Biobank of the Fundació per la Investigació Germans Trias i Pujol and the research ethics committee of the Hospital Universitari Germans Trias i Pujol (No. PI-15–044).

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Fernández-Figueras, M.T., Carrato, C., Saenz-Sardà, X. et al. MicroRNA31 and MMP-1 contribute to the differentiated pathway of invasion -with enhanced epithelial-to-mesenchymal transition- in squamous cell carcinoma of the skin. Arch Dermatol Res 314, 767–775 (2022). https://doi.org/10.1007/s00403-021-02288-x

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  • DOI: https://doi.org/10.1007/s00403-021-02288-x

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