Complement Component C3 and Complement Factor B Promote Growth of Cutaneous Squamous Cell Carcinoma

• DOI: 10.1016/j.ajpath.2017.01.006
• Publication Date: 2017-03-17T06:00:27Z
• Authors: Pilvi Riihilä; Liisa Nissinen; Mehdi Farshchian; Markku Kallajoki; Atte Kivisaari; Seppo Meri; Reidar Grénman; Sirkku Peltonen; Juha Peltonen; Taina Pihlajaniemi; Ritva Heljasvaara; Veli-Matti Kähäri
• Keywords: EXPRESSION; skin; FACTOR-H; Skin Neoplasms; Carcinogenesis; Mice, Inbred A; FACTOR-I; alternative pathway; Mice, Nude; PROGRESSION; ALTERNATIVE PATHWAY; Pathology and Forensic Medicine; ACTIVATION; 03 medical and health sciences; LUNG-CANCER; Cell Movement; Cell Line, Tumor; expression; tumor microenvironment; Animals; Humans; Aged; Cell Proliferation; Aged, 80 and over; 0303 health sciences; HUMAN KERATINOCYTES; Complement C3; Middle Aged; ta3122; ta3125; Up-Regulation; 3. Good health; Biomedicine; human keratinocytes; Case-Control Studies; lung-cancer; Carcinoma, Squamous Cell; factor-I; Heterografts; activation; Female; progression; TUMOR MICROENVIRONMENT; SKIN; Neoplasm Transplantation; factor-H; Complement Factor B

Cutaneous squamous cell carcinoma (cSCC) is one of the most common metastatic skin cancers with increasing incidence. We examined the roles of complement component C3 and complement factor B (CFB) in the growth of cSCC. Analysis of cSCC cell lines (n = 8) and normal human epidermal keratinocytes (n = 11) with real-time quantitative PCR and Western blotting revealed up-regulation of C3 and CFB expression in cSCC cells. Immunohistochemical staining revealed stronger tumor cell-specific labeling for C3 and CFB in invasive cSCCs (n = 71) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n = 11) than in cSCC in situ (n = 69), actinic keratoses (n = 63), and normal skin (n = 5). Significant up-regulation of C3 and CFB mRNA expression was noted in chemically induced mouse cSCCs, compared to benign papillomas. Knockdown of C3 and CFB expression inhibited migration and proliferation of cSCC cells and resulted in potent inhibition of extracellular signal-regulated kinase 1/2 activation. Knockdown of C3 and CFB markedly inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the roles of C3 and CFB in the development of cSCC and identify them as biomarkers and potential therapeutic targets in this metastatic skin cancer.