The role of keratinocytic RXR[alpha] in regulating melanocyte homeostasis and carcinogen induced melanomagenesis Public Deposited

The role of keratinocytic RXRα in regulating melanocyte homeostasis and carcinogen induced melanomagenesis

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/hq37vs58q

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  • Cutaneous melanoma remains the deadliest form of skin cancer, with a diagnosis of metastasis indicating a median survival rate of less than a year. Solar ultraviolet (UV) radiation, especially childhood sun exposure, is an important etiological risk factor of melanoma. Previous studies determined that mice selectively lacking the nuclear hormone receptor Retinoid X Receptor α in epidermal keratinocytes (RXRα[superscript ep-/-]) developed a higher number of aggressive melanocytic tumors compared to wild type mice after two-step chemical carcinogenesis, suggesting a novel role of keratinocytic nuclear receptor signalling during melanoma progression. We then discovered a progressive loss of RXRα expression in epidermal keratinocytes during melanoma progression in humans. We also investigated the contributions of CDK4[superscript R24C/R24C] and keratinocytic RXRα to influence metastatic progression in a mouse model by generating RXRα[superscript ep-/-]/CDK4[superscript R24C/R24C] bigenic mice containing an activated cyclin dependent kinase 4 (CDK4), besides lacking RXRα in epidermal keratinocytes. Those bigenic mice developed malignant melanomas that metastasized to regional lymph nodes after carcinogen exposure. Expression of several keratinocyte-derived growth factors implicated in melanomagenesis were upregulated in the skin of bigenic mice, and recruitment of RXRα was shown on the promoters of endothelin-1 (Edn1) and hepatocyte growth factor (Hgf). We then confirmed a downregulation of factors (FAS, E-cadherin and PTEN) implicated in apoptosis, invasion and survival within the melanocytic tumors. To further evaluate the paracrine role that EDN1 has on melanocyte activation, we utilized a transgenic mouse model where the gene encoding Edn1 was selectively ablated from epidermal keratinocytes using the Cre-LoxP strategy to create the EDN1[superscript ep-/-] knockout mouse line. We discovered a direct in vivo transcriptional regulation of keratinocytic Edn1 by the tumor-suppressor p53 in epidermal keratinocytes in response to UV irradiation. We also demonstrate that in vivo disruption of keratinocyte-derived EDN1 signaling alters melanocyte proliferation and decreases epidermal and dermal melanocyte populations in both normal and UV exposed mouse skin. EDN1 also has a protective role against UVR-induced DNA damage and apoptosis and similar effects on UV-induced melanocyte proliferation and DNA damage are observed in p53-null mice. Inhibition of EDN1 signaling by topical application of an EDNRB antagonist BQ788 on mouse skin also recapitulates epidermal EDN1 ablation. Furthermore, treatment of primary murine melanocytes with BQ788 abrogates signaling downstream of this receptor. Taken together, these studies demonstrate the contribution of RXRα regulated keratinocytic paracrine signaling during the cellular transformation and malignant conversion of melanocytes. Also, they establish an essential role of EDN1 in epidermal keratinocytes to mediate UV-induced melanocyte homeostasis in vivo.
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