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Melanoma May Be Triggered by Deficit of Retinoid-X-Receptors in Melanocytes

By BiotechDaily International staff writers
Posted on 20 May 2014
Image: Arup and Gitali Indra are beginning to find clues to predicting, preventing and stopping melanoma before it spreads (Photo courtesy of Karl Maasdam / Oregon State University College of Pharmacy).
Image: Arup and Gitali Indra are beginning to find clues to predicting, preventing and stopping melanoma before it spreads (Photo courtesy of Karl Maasdam / Oregon State University College of Pharmacy).
Cancer researchers have linked the development of the deadly skin cancer melanoma to depressed expression in melanocytes of the type II nuclear receptors Retinoid-X-Receptor alpha (RXRalpha) and Retinoid-X-Receptor beta (RXRbeta).

Melanoma is the deadliest form of skin cancer. It derives from melanocytes, the melanin-producing cells of the skin, which give the skin its tone in addition to protecting it from harmful effects of ultraviolet radiation (UVR). Changes in the skin microenvironment, such as signaling from other cell types, can influence melanoma progression. While several key genes in melanoma development have been identified, the underlying mechanisms are complex; different combinations of mutations can result in melanoma formation and genetic profiles of tumors can vary greatly among patients.

Retinoid X receptors (RXRs) are nuclear receptors that mediate the biological effects of retinoids (vitamin A derivatives) by their involvement in retinoic acid-mediated gene activation. These receptors function as transcription factors by binding as homodimers or heterodimers to specific sequences in the promoters of target genes. The protein encoded by this gene is a member of the steroid and thyroid hormone receptor superfamily of transcriptional regulators.

Since expression of RXRalpha disappears during melanoma progression in humans, investigators at Oregon State University (Corvallis, USA) developed a tissue-specific gene ablation strategy to characterize the role of these type II nuclear receptors in melanocytes to control UVR-induced skin immune responses and cell survival.

They reported in the May 8, 2014, online edition of the journal PLoS Genetics that melanocytes in mice with melanocyte-specific ablation of RXRalpha and RXRbeta attracted fewer IFN-gamma (interferon-gamma) secreting immune cells than in wild-type mice following acute UVR exposure, via altered expression of several chemoattractive and chemorepulsive chemokines/cytokines. Reduced IFN-gamma in the microenvironment altered UVR-induced apoptosis, and due to this, the survival of surrounding dermal fibroblasts was significantly decreased in mice lacking RXRalpha/beta.

These results emphasized a novel immunomodulatory role for melanocytes in controlling survival of neighboring cell types besides controlling their own, and identified RXRs as potential targets for therapy against UV induced melanoma.

"We believe this is a breakthrough in understanding exactly what leads to cancer formation in melanoma," said senior author Dr. Arup Indra, associate professor of pharmacology at Oregon State University. "We have found that some of the mechanisms which ordinarily prevent cancer are being switched around and actually help promote it. When there is not enough RXR, the melanocytes that exist to help shield against cancer ultimately become part of the problem. It is routine to have genetic damage from sunlight, because normally those cells can be repaired or killed if necessary. It is the breakdown of these control processes that result in cancer, and that happens when RXR levels get too low. It is quite possible that a new and effective therapy can now be developed, based on increasing levels of RXR."

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