Abstract
The second most common cancer in humans, cutaneous squamous cell carcinoma (cSCC), affects more than 1 million patients a year in the United States. cSCC arise from keratinocytes of the epidermis or hair follicles. Current treatments are limited, especially for pre-cancerous lesions. Homeostasis and differentiation of the skin is regulated through calcium-associated signaling. Better understanding the role of calcium regulation in the epidermis and its relation to the progression of skin cancer could be important in finding new interventions. Protein isoforms called hFWE3 and hFWE4 have been implicated in both calcium signaling and the progression of cancer, both of which are compromised in cSCC, through a process called cell competition. In breast cancer cells, cells expressing hFWE4 isoforms out-compete cells expressing hFWE3 isoforms and promote the progression of tumor growth. We hypothesized that hFWE4 would act similarly in cSCC cells, out-competing cells over-expressing hFWE3 and promoting the progression of cSCC. Interestingly, when hFWE3 and hFWE4 over-expressing cSCC cells were co-cultured together no significant cell competition was observed. RNA-seq analysis revealed that transcript and protein expression of S100A7, S100A8, and S100A9 were decreased in hFWE3 and hFWE4 over-expressing cells. Transcripts for these S100 isoforms were strikingly increased in human cSCC compared to normal skin. Exposure of cSCC cells to stress stimuli including ultraviolet irradiation, serum starvation, reactive oxygen species, or 5-fluorouracil increased hFWE expression, suggesting hFWE may be involved in the cellular stress response. Taken together, these results document a strong correlation between hFWE expression, S100 regulation, and regulation of epidermal differentiation and stress response.