The
proprotein convertases (PCs)
furin and PACE4 process numerous substrates involved in
tumor growth, invasion, and
metastasis. We have previously shown that PCs increase the susceptibility to chemical skin
carcinogenesis. Because of the human relevancy of UV radiation in the etiopathogenesis of human
skin cancer, we investigated whether or not transgenic mice overexpressing either
furin alone or both
furin and PACE4 show increased susceptibility to UV
carcinogenesis. After backcrossing our previously described
furin and PACE4 transgenic lines, targeted to the epidermis, into a SKH-1 background, we exposed both single and double transgenic mice to UV radiation for 34 weeks. The results showed an increase in
squamous cell carcinoma (SCC) multiplicity of approximately 70% in the single
furin transgenic mouse line SF47 (P < .002) and a 30% increase in the other single transgenic line SF49 when compared to wild-type (WT) SKH-1 mice. Interestingly, there was also an increase in the percentage of high histologic grade SCCs in the transgenic lines compared to the WT mice, i.e., WT = 9%, SF47 = 15%, and SF49 = 26% (P < .02). Targeting both
furin and PACE4 to the epidermis in double transgenic mice did not have an additive effect on
tumor incidence/multiplicity but did enhance the
tumor histopathologic grade, i.e., a significant increase in higher grade SCCs was seen in the bigenic mouse line SPF47 (P < .02). Thus, we observed an increased susceptibility to UV in single
furin transgenic mice that was not substantially enhanced in the double
furin/PACE4 transgenic mice.