The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing globally. We have studied the expression of complement system components in cSCC. Expression profiling of cSCC cell lines (n=8) and normal human epidermal keratinocytes (n=5) with Affymetrix and quantitative real-time PCR (qPCR) revealed upregulation of complement factor H (CFH) and factor H-like protein-1 (FHL-1) in cSCC cell lines. The expression of CFH and FHL-1 mRNAs was also significantly higher in cSCC tumors (n=6) than in normal skin (n=11). Analysis of CFH and FHL-1 expression in vivo in invasive cSCCs (n=65), in situ cSCCs (n=38), and premalignant lesions (actinic keratoses, n=37) by immunohistochemistry showed that they were specifically expressed by tumor cells in cSCCs and the staining intensity was stronger in cSCCs than in in situ cSCCs and actinic keratoses. The expression of CFH by cSCC cells was upregulated by IFN-γ and the basal CFH and FHL-1 expression was dependent on extracellular signal–regulated kinase (ERK)1/2 and p38 signaling. Knockdown of CFH and FHL-1 expression inhibited proliferation and migration of cSCC cells and inhibited basal ERK1/2 activation. These results provide evidence for a role of CFH and FHL-1 in cSCC progression and identify them as progression markers and potential therapeutic targets in SCCs of skin.

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.

Skin cancers are the most common types of cancer worldwide, and their incidence is increasing. Melanoma, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC) are the three major types of skin cancer. Melanoma originates from melanocytes, whereas BCC and cSCC originate from epidermal keratinocytes and are therefore called keratinocyte carcinomas. Chronic exposure to ultraviolet radiation (UVR) is a common risk factor for skin cancers, but they differ with respect to oncogenic mutational profiles and alterations in cellular signaling pathways. cSCC is the most common metastatic skin cancer, and it is associated with poor prognosis in the advanced stage. An important early event in cSCC development is mutation of the TP53 gene and inactivation of the tumor suppressor function of the tumor protein 53 gene (TP53) in epidermal keratinocytes, which then leads to accumulation of additional oncogenic mutations. Additional genomic and proteomic alterations are required for the progression of premalignant lesion, actinic keratosis, to invasive and metastatic cSCC. Recently, the role of p53 in the invasion of cSCC has also been elucidated. In this review, the role of p53 in the progression of cSCC and as potential new therapeutic target for cSCC will be discussed.

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.

Tumor cell-specific AIM2 regulates growth and invasion of cutaneous squamous cell carcinoma Tumor cell-specific AIM2 regulates growth and invasion of cutaneous squamous cell carcinoma