Elimination of KLK5 inhibits early skin tumorigenesis by reducing epidermal proteolysis and reinforcing epidermal microstructure

Biochimica Et Biophysica Acta. Molecular Basis of Disease
Georgios PampalakisGeorgia Sotiropoulou

Abstract

Epidermal desquamation involves a finely-tuned proteolytic cascade ensuring the regulated cleavage of desmosomes that releases old stratum corneum outermost layers. Although the roles of desmosomes in normal physiology are well-established, their putative involvement in cancer remains unexplored. The KLK5 protease is thought of having fundamental roles in epidermal proteolysis and homeostasis, and its aberrant activity has been linked to skin pathologies. We found that deletion of Klk5 results in significantly higher numbers of lengthier desmosomes and enhanced skin strength. Klk5-/- mice retained normal skin barrier function and are resistant to chemically-induced skin tumorigenesis. The resistance to tumorigenesis was not due to inhibition of inflammation, and on the contrary, absence of Klk5 increased the TPA-induced inflammatory skin response. We found that increased desmosomes and reduced proteolysis prevent oncogenic signaling by capturing β-catenin into the cytoplasm and facilitate epidermal keratinocyte apoptosis, thus, inhibiting tumor initiation. We highlight that the skin ultrastructure affects early neoplastic transformation by modulating intracellular signaling and suggest that tissue reinforcement provides a novel...Continue Reading

Citations

Jan 9, 2020·The Journal of Dermatology·Eleni ZingkouGeorgia Sotiropoulou
Feb 6, 2021·Experimental Dermatology·Georgia SotiropoulouGeorgios Pampalakis
Aug 31, 2021·Cellular and Molecular Life Sciences : CMLS·Georgios PampalakisGeorgia Sotiropoulou

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