Pro-Carcinogenic Implications of Folic Acid Supplementation During Chemically Induced Cutaneous Squamous Cell Carcinoma in Mice

In light of the increasing exposure to folate and its unresolved relationship with skin cancer, experimental studies are warranted to better understand and define its role in skin carcinogenesis. The present study evaluated the effects of folic acid supplementation on cutaneous squamous cell carcinoma (cSCC) in mice and explored the underlying mechanisms. A two-stage skin carcinogenesis model was employed using 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoyl phorbol-13-acetate (TPA) as initiator and tumor promoter respectively. LACA mice were orally supplemented with folic acid (FA) at doses of 1 or 2 mg/kg body weight and divided into six groups: control, DMBA/TPA, FA1(1 mg/kg) + DMBA/TPA, FA2(2 mg/kg) + DMBA/TPA, FA1 and FA2 groups. Supplementation began 4 weeks prior to tumor induction and continued for twenty weeks. Histopathological analysis confirmed cSCC development. During the early stages, papilloma incidence was higher in FA1 + DMBA/TPA and FA2 + DMBA/TPA groups in comparison to DMBA/TPA group. However, by the end of the treatment period, lesion incidence reached 100% in all groups, with a greater total lesion count and lesion burden observed in the supplemented groups its indicating pro-carcinogenic effects. Enhanced cellular proliferation in these groups was evident from histomorphometric assessments and increased expression of proliferating cell nuclear antigen and folate transporters. Increase in tumorigenesis was also associated with enhanced activity of serum lactate dehydrogenase, oxidative DNA damage and inhibition in expression of MGMT gene. However, no noteworthy difference was observed between two levels of supplementation. These findings suggest that folic acid supplementation may promote skin tumorigenesis through increased proliferation, enhanced DNA damage, and impaired DNA repair mechanisms.