Complement Factor I Promotes Progression of Cutaneous Squamous Cell Carcinoma

Abstract

The incidence of cutaneous squamous cell carcinoma (cSCC) is rising worldwide. We have examined the role of complement components in the progression of cSCC. Analysis of cSCC cell lines (n=8) and normal human epidermal keratinocytes (n=11) with whole transcriptome profiling (SOLiD), quantitative real-time reverse transcriptase-PCR, and western blotting revealed marked overexpression of complement factor I (CFI) in cSCC cells. Immunohistochemical analysis for CFI in vivo showed stronger tumor cell-specific labeling intensity in invasive sporadic cSCCs (n=83) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n=7) than in cSCC in situ (n=65), premalignant epidermal lesions (actinic keratoses, n=64), benign epidermal papillomas (seborrheic keratoses, n=39), and normal skin (n=9). The expression of CFI was higher in the aggressive Ha-ras-transformed cell line (RT3) than in less tumorigenic HaCaT cell lines (HaCaT, A5, and II-4). The expression of CFI by cSCC cells was upregulated by IFN-γ and IL-1β. Knockdown of CFI expression inhibited proliferation and migration of cSCC cells and resulted in inhibition of basal extracellular signal-regulated kinase (ERK) 1/2 activation. Knockdown of CFI expression potently inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the role of CFI in the progression of cSCC and identify it as a potential therapeutic target in this nonmelanoma skin cancer.

Local expression of complement factor I in breast cancer cells correlates with poor survival and recurrence

“…Interestingly for our study, FH is one of the main cofactors required for the activity of FI. Of note, there is only one study showing FI production by tumor cells in vivo in cutaneous squamous cell carcinoma [16] where there was association of FI staining intensity with aggressive tumor phenotype [16]. Previously we reported that non-small lung cancer (NSCLC) cell lines secrete several soluble complement inhibitors: FI and its cofactors FH and C4BP [15].…”

“…Interaction of iC3b with its cellular receptors edits the immune response and influences local inflammation, which in turn may exert both pro-and antitumor effects [10]. While expression of FI was reported in a number of tumor cell lines including those originating from hepatoma [11], B cell leukemia [12], glioma [13], rhabdosarcoma [14] lung cancer [15] and cutaneous squamous cell carcinoma [16], only the latter study describes expression of FI by tumor cells of the skin in vivo and shows association of FI production and aggressive tumor phenotype [16]. Herein, we report local 4 production of FI in breast cancer cells and associations between tumor-derived FI and clinical data obtained from 130 breast cancer patients.…”

The dual role of complement in cancer and its implication in anti-tumor therapy

“…Although the primary site of factor I production is the liver, Okroj et al (88) have shown that functionally active factor I is produced and secreted by some NSCLCs and that, together with C4BP, leads to decreased C3b deposition thus limiting complement-dependent lysis. Moreover, in a recent report, factor I was detected in cutaneous squamous cell carcinomas and its expression was positively associated with tumor aggressiveness (124).…”

Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression

“…Although mostly moderately progressive and easily resectable, approximately 4% of cSCCs metastasize (1). Besides UV irradiation as the major cause of cSCC in the general population (2), also chronic inflammation, scarring, papilloma virus infection, or genetic factors have been postulated to contribute (1,3).…”