Mechanisms of clock gene modulation by UVA radiation and visible light in normal (Melan-a) and transformed (B16-F10) melanocytes

Author(s)

Leonardo Vinícius Monteiro de Assis

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB)
• Defense date: 2019-02-22

Examining board members

Ana Maria de Lauro Castrucci; Mauricio da Silva Baptista; Miguel Luiz Batista Junior; Silvya Stuchi Maria Engler

• Advisor: Ana Maria de Lauro Castrucci

Abstract

The skin has a system that can detect light in a fashion similar to the retina. Although its presence was initially reported almost 20 years ago, only in 2011 functional studies started to be reported. The biological clock of the skin has also been reported in the beginning of the century, but its function and relevance still remain unexplored. Thus, this Ph.D. project was designed to explore the functionality of both systems in melanocytes, and whether the disruption of these systems is associated with the development of melanoma cancer. Using in vitro, in vivo, and bioinformatics approaches, we have shown that: 1) the biological clock of malignant melanocytes is more responsive to visible light, UVA radiation, estradiol, and temperature compared to normal cells; 2) UVA radiation is detected by melanopsin (OPN4) and rhodopsin (OPN2), which triggers a cGMP related cascade that leads to immediate pigment darkening (IPD) in normal and malignant melanocytes; 3) in addition to detecting UVA radiation, OPN4 also senses thermal energy, which activates the biological clock of both normal and malignant melanocytes; 4) regarding the biological clock, we have provided several layers of evidence that proves that in melanoma a chronodisruption scenario is established compared to healthy skin and/or normal pigment cells; 5) in vivo tumor samples display a low amplitude circadian rhythm of clock gene expression and an ultradian oscillatory profile in melanin content; 6) a non-metastatic melanoma leads to a systemic chronodisruption, which we suggest that could favor the metastatic process; 7) in human melanoma, we demonstrated the role of BMAL1 as a prognostic marker and a putative marker of immune therapy success. Taken altogether, these results significantly contributed to the literature as it brought to light new and interesting targets and processes, which will be explored in future projects (AU)

• FAPESP's process: 13/24337-4 - Clock genes modulation by UVA/blue light stimulation in normal melan-A and transformed B-16 melanocytes
• Grantee: Leonardo Vinícius Monteiro de Assis
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)