Tumour‐cell‐derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma

Abstract

Summary Background The incidence of epidermal keratinocyte‐derived cutaneous squamous cell carcinoma (cSCC) is increasing worldwide. Objectives To study the role of the complement classical pathway components C1q, C1r and C1s in the progression of cSCC. Methods 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. Results 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. Conclusions 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. 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. What is the translational message? Our results identify complement classical pathway components C1r and C1s as biomarkers and putative therapeutic targets in cSCC.

Water-Pipe Smoking Exposure Deregulates a Set of Genes Associated with Human Head and Neck Cancer Development and Prognosis

“…Although C1R is known to regulate the complement pathway of the innate immune system, in this study, we found upregulated CIR expression in HNSCC. This is in concordance with a previous study that correlated the expression of C1R in cutaneous SCC (cSCC) with tumor progression, cell proliferation, and migration [ 67 , 68 ]. Since cSCC lesions frequently develop in the HN region [ 69 ], our data correlate with this finding.…”

“…Since cSCC lesions frequently develop in the HN region [ 69 ], our data correlate with this finding. Although, the prognostic relevance of C1R has not been studied in cancer; however, it is associated with tumor progression and migration [ 67 , 68 ], hence our data suggest a significant correlation between C1R and shorter RFS. Furthermore, our data implicate the other member of the complement pathway, MASP-2 gene, which is upregulated in oral epithelial cells exposed to WPS.…”

Tumour serine proteases C1r and C1s as novel biomarkers and therapeutic targets in invasive sporadic and recessive dystrophic epidermolysis bullosa‐associated cutaneous squamous cell carcinoma

“…The authors show that C1r and C1s expression is markedly elevated in invasive sporadic and RDEB‐associated cSCC while their knockdown in cSCC cells inhibited activation of the extracellular signal‐related kinase (ERK) 1/2 and Akt pathway, promoted cSCC apoptosis, and suppressed growth and vascularization of human cSCC xenograft tumours in vivo . Interestingly, RDEB‐SCC sections had the strongest C1r and C1s staining, and the knockdown of C1r and C1s upregulated the production of matrix metalloproteinase‐9 in cSCC cells . Additionally, previous studies have shown that extracellular C1s can cleave and inactivate alarmin high‐mobility group box (HMGB1), hence regulating inflammation and suppressing proinflammatory cytokine production .…”

“…This issue of the BJD includes an interesting study by Riihila et al ., identifying novel specific biomarkers of invasive sporadic and recessive dystrophic epidermolysis bullosa (RDEB)‐associated cutaneous squamous cell carcinoma (cSCC) . This is a significant finding, as no biomarkers are currently in clinical use to predict cSCC aggressiveness.…”

“…report tumour‐cell‐derived serine proteases, C1r and C1s, known initiators of the classical pathway activation of the complement system, to be novel biomarkers and putative therapeutic targets in cSCC . The authors show that C1r and C1s expression is markedly elevated in invasive sporadic and RDEB‐associated cSCC while their knockdown in cSCC cells inhibited activation of the extracellular signal‐related kinase (ERK) 1/2 and Akt pathway, promoted cSCC apoptosis, and suppressed growth and vascularization of human cSCC xenograft tumours in vivo . Interestingly, RDEB‐SCC sections had the strongest C1r and C1s staining, and the knockdown of C1r and C1s upregulated the production of matrix metalloproteinase‐9 in cSCC cells .…”