Tumor cell-derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma

P Riihilä, K Viiklepp, L Nissinen, M Farshchian, M Kallajoki, A Kivisaari, S Meri, J Peltonen, S Peltonen, V-M Kähäri
British Journal of Dermatology 2019 May 3

BACKGROUND: Incidence of epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is increasing worldwide.

OBJECTIVES: To study the role of complement classical pathway components C1q, C1r and C1s in the progression of cSCC.

METHODS: The mRNA levels of C1Q subunits, C1R and C1S in cSCC cell lines, normal human epidermal keratinocytes (NHEKs), cSCC tumors in vivo and normal skin were analyzed with quantitative RT-PCR. The production of C1r and C1s was determined with Western blotting. The expression of C1r and C1s in tissue samples in vivo was analyzed with immunohistochemistry and further investigated in human cSCC xenografts by knocking down C1r and C1s.

RESULTS: Significantly elevated C1R and C1S mRNA levels and production of C1r and C1s were detected in cSCC cells, compared to normal human epidermal keratinocytes. The mRNA levels of C1R and C1S were markedly elevated in cSCC tumors in vivo compared to normal skin. Abundant expression of C1r and C1s by tumor 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 ERK1/2 and Akt, promoted apoptosis of cSCC cells and significantly suppressed growth and vascularization of human cSCC xenograft tumors in vivo.

CONCLUSIONS: These results provide evidence for the role of tumor cell-derived C1r and C1s in the progression of cSCC and identify them as biomarkers and putative therapeutic targets in cSCC. This article is protected by copyright. All rights reserved.

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