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Published on: December 19, 2019
Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation
Yira Bermudez1, Claudia A Benavente, Ralph G Meyer
1Arizona Cancer Center and Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
Background:
Chronic UV skin exposure leads to epidermal differentiation defects in humans that can be largely restored by pharmacological doses of nicotinic acid. Nicotinic acid has been identified as a ligand for the human G-protein-coupled receptors GPR109A and GPR109B that signal through G(i)-mediated inhibition of adenylyl cyclase. We have examined the expression, cellular distribution, and functionality of GPR109A/B in human skin and skin derived epidermal cells.
Results:
Nicotinic acid increases epidermal differentiation in photodamaged human skin as judged by the terminal differentiation markers caspase 14 and filaggrin. Both GPR109A and GPR109B genes are transcribed in human skin and in epidermal keratinocytes, but expression in dermal fibroblasts is below limits of detection. Receptor transcripts are greatly over-expressed in squamous cell cancers. Receptor protein in normal skin is prominent from the basal through granular layers of the epidermis, with cellular localization more dispersive in the basal layer but predominantly localized at the plasma membrane in more differentiated epidermal layers. In normal human primary and immortalized keratinocytes, nicotinic acid receptors show plasma membrane localization and functional G(i)-mediated signaling. In contrast, in a squamous cell carcinoma derived cell line, receptor protein shows a more diffuse cellular localization and the receptors are nearly non-functional.
Conclusions:
The results of these studies justify future genetic and pharmacological intervention studies to define possible specific role(s) of nicotinic acid receptors in human skin homeostasis.
Insights
Nicotinic acid improves skin differentiation by activating GPR109A/B receptors in human skin. These receptors are functional in normal skin but impaired in squamous cell carcinoma, suggesting a role in skin homeostasis.
Area of Science:
- Dermatology
- Molecular Biology
- Biochemistry
Background:
- Chronic UV exposure causes epidermal differentiation defects in human skin.
- Nicotinic acid, a ligand for GPR109A/B receptors, can restore these defects.
- GPR109A/B signal via G(i)-mediated inhibition of adenylyl cyclase.
Purpose of the Study:
- To investigate the expression, cellular distribution, and functionality of GPR109A/B in human skin.
- To understand the role of nicotinic acid receptors in skin homeostasis and photodamage.
- To compare receptor characteristics in normal skin versus squamous cell carcinoma.
Main Methods:
- Analysis of GPR109A/B gene transcription in human skin and epidermal cells.
- Immunohistochemical examination of receptor protein distribution in skin layers.
- Functional assays of G(i)-mediated signaling in keratinocytes and cancer cell lines.
Main Results:
- Nicotinic acid enhances epidermal differentiation markers (caspase 14, filaggrin) in photodamaged skin.
- GPR109A/B are transcribed in skin and keratinocytes, but not dermal fibroblasts.
- Receptors are over-expressed in squamous cell cancers, with altered localization and impaired function.
Conclusions:
- Nicotinic acid receptors are present and functional in normal human epidermis.
- Altered receptor expression and function in squamous cell carcinoma suggest a role in cancer development.
- Further research is warranted to explore nicotinic acid receptor roles in skin homeostasis and disease.
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