Clock-related genes disruption and melatonin administration are associated with melanoma and oral cancer, but not with skin carcinoma

Abstract

Melatonin plays an important role in the regulation of circadian clock genes, whose deregulation contributes to cancer development. In this study, we first performed a bioinformatic analysis for melanoma, non-melanoma skin cancer, and oral squamous cell carcinoma to evaluate what clock-related genes are deregulated when compared to normal tissue. Further, we administrated melatonin in cell cultures for cutaneous squamous cell carcinoma, skin melanoma, and oral squamous cell carcinoma to observe changes in cancer cell phenotypes. Later, we evaluated gene expressions associated to clock genes, cancer cell proliferation, migration, invasion, and apoptosis. In summary, clock-related genes are deregulated in both cancers. Skin melanoma and oral cancer presented commonly deregulated clock related genes and were associated with poor survival and chemoresistance, according to bioinformatic analysis. In cell culture, melatonin administration increased Per2, Cry1, Cry2 and Bmal1 mRNA expression levels and decreased Clock gene mRNA levels. Per2, Cry1, Cry2, and Bmal1 genes belong to tumor suppressor genes that can control cell proliferation, cell death, DNA damage, and repair system. Te hypothesized that changes in the expression of clock related-genes in cancer could be responsible for metabolic changes that could lead to the cancer aggressiveness. Melatonin administration showed changes in melanoma and oral cancer phenotypes. Melatonin also seems to influence melanoma and oral tumor progression through Mki67, Hif-1a, Vegfa, Col1a1, Cdh1, Casp3, Bax, Bcl2, Mmp9, Per2, Cry1, Cry2, Bmal1 and Clock modulation.