Roles for retinoid-X-receptors in solar UV-induced melanocyte homeostasis and melanomagenesis Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/1831cp34w

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  • Melanoma is the deadliest form of skin cancer, arising from malignant transformation of pigment-producing melanocytes. The primary risk factor for melanoma and other skin cancers is DNA damage resulting from unprotected solar ultraviolet radiation (UVR). If incorrectly repaired, this damage can result in incorporation of mutations that cause aberrant cell cycling and/or other functional defects that promote tumorigenesis. Rates of melanoma incidence are on the rise in Oregon and throughout the U.S.; thus better understanding of the molecular mechanisms underlying its formation and progression are needed for the purposes of diagnosis and therapeutic targeting. In this work we have used mouse models to establish multiple roles for Retinoid-X-Receptors (RXRs) in UVR-induced melanocyte homeostasis and melanomagenesis. Ablation of RXRα expression in epidermal keratinocytes (Rxrα[superscript ep-/-]) enhances melanocyte proliferation following an acute UVR dose; stemming from increased expression of mitogenic paracrine factors. Combining Rxrα[superscript ep-/-] mice with activated CDK4 (R24C) or oncogenic NRAS (Q61K) mutations in a bigenic model results in enhanced UVR-induced melanomagenesis compared to control mice with the CDK4 or NRAS mutations alone. These melanomas show increased expression of malignant melanoma and tumor angiogenesis markers; and increased metastases of pigment-producing cells to draining lymph nodes. Interestingly, the tumor adjacent normal skin of these mice have reduced expression of p53 and PTEN, tumor suppressors commonly downregulated in melanoma; suggesting that in addition to enhancing melanomagenesis, keratinocytic RXRα loss results in a microenvironment favorable to primary tumor formation. By ablating RXRs α and β specifically in the melanocytes (Rxrα/β[superscript mel-/-]), we observed differential alterations in the post-UVR survival of the melanocytes and the dermal fibroblasts. Loss of melanocytic RXR expression results in defective homeostasis of chemoattractive/chemorepulsive chemokines secreted by melanocytes to attract macrophages and other immune cells post-UVR. An overall reduction of immune cell infiltration in Rxrα/β[superscript mel-/-] mice results in less available interferon-γ available in the microenvironment which has a negative effect on post-UVR survival of fibroblasts and melanocytes. However, as the genetic defect in these mice is specifically in the melanocytes, there are dysregulations in cell-intrinsic apoptosis signaling that allow these cells to overcome reduced available IFN-γ and have enhanced survival post-UVR. Therefore RXRs in melanocytes modulate post-UVR survival of dermal fibroblasts in a "non-cell autonomous" manner, underscoring their role in immune surveillance; while independently mediating post-UVR melanocyte survival in a "cell autonomous" manner. Altogether these results establish a multitude of roles for RXRs in melanocyte homeostasis and melanomagenesis, and identifies them as potential targets for melanoma diagnosis and therapeutics.
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