The acid-sensing ion channels ASIC1 and ASIC2, as well as the transient receptor potential vanilloid channels TRPV1 and TRPV4, are proton-gated cation channels that can be activated by low extracellular pH (pHe), which is a hallmark of the tumor microenvironment in solid tumors.,However, the role of these channels in the development of skin tumors is still unclear.,In this study, we investigated the expression profiles of ASIC1, ASIC2, TRPV1 and TRPV4 in malignant melanoma (MM), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and in nevus cell nevi (NCN).,We conducted immunohistochemistry using paraffin-embedded tissue samples from patients and found that most skin tumors express ASIC1/2 and TRPV1/4.,Striking results were that BCCs are often negative for ASIC2, while nearly all SCCs express this marker.,Epidermal MM sometimes seem to lack ASIC1 in contrast to NCN.,Dermal portions of MM show strong expression of TRPV1 more frequently than dermal NCN portions.,Some NCN show a decreasing ASIC1/2 expression in deeper dermal tumor tissue, while MM seem to not lose ASIC1/2 in deeper dermal portions.,ASIC1, ASIC2, TRPV1 and TRPV4 in skin tumors might be involved in tumor progression, thus being potential diagnostic and therapeutic targets.
The incidence of epidermal keratinocyte‐derived cutaneous squamous cell carcinoma (cSCC) is increasing worldwide.,To study the role of the complement classical pathway components C1q, C1r and C1s in the progression of cSCC.,The mRNA levels of C1Q subunits and C1R and C1S in cSCC cell lines, normal human epidermal keratinocytes, cSCC tumours in vivo and normal skin were analysed with quantitative real‐time polymerase chain reaction.,The production of C1r and C1s was determined with Western blotting.,The expression of C1r and C1s in tissue samples in vivo was analysed with immunohistochemistry and further investigated in human cSCC xenografts by knocking down C1r and C1s.,Significantly elevated C1R and C1S mRNA levels and production of C1r and C1s were detected in cSCC cells, compared with normal human epidermal keratinocytes.,The mRNA levels of C1R and C1S were markedly elevated in cSCC tumours in vivo compared with normal skin.,Abundant expression of C1r and C1s by tumour cells was detected in invasive sporadic cSCCs and recessive dystrophic epidermolysis bullosa‐associated cSCCs, whereas the expression of C1r and C1s was lower in cSCC in situ, actinic keratosis and normal skin.,Knockdown of C1r and C1s expression in cSCC cells inhibited activation of extracellular signal‐related kinase 1/2 and Akt, promoted apoptosis of cSCC cells and significantly suppressed growth and vascularization of human cSCC xenograft tumours in vivo.,These results provide evidence for the role of tumour‐cell‐derived C1r and C1s in the progression of cSCC and identify them as biomarkers and putative therapeutic targets in cSCC.,What's already known about this topic?,The incidences of actinic keratosis, cutaneous squamous cell carcinoma (cSCC) in situ and invasive cSCC are increasing globally.Few specific biomarkers for progression of cSCC have been identified, and no biological markers are in clinical use to predict the aggressiveness of actinic keratosis, cSCC in situ and invasive cSCC.,The incidences of actinic keratosis, cutaneous squamous cell carcinoma (cSCC) in situ and invasive cSCC are increasing globally.,Few specific biomarkers for progression of cSCC have been identified, and no biological markers are in clinical use to predict the aggressiveness of actinic keratosis, cSCC in situ and invasive cSCC.,What does this study add?,Our results provide novel evidence for the role of complement classical pathway components C1r and C1s in the progression of cSCC.,Our results provide novel evidence for the role of complement classical pathway components C1r and C1s in the progression of cSCC.,What is the translational message?,Our results identify complement classical pathway components C1r and C1s as biomarkers and putative therapeutic targets in cSCC.,Our results identify complement classical pathway components C1r and C1s as biomarkers and putative therapeutic targets in cSCC.,Linked Comment: https://doi.org/10.1111/bjd.18419.,https://doi.org/10.1111/bjd.18821 available online