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. / Graduation date: 2013
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/36265 |
| Date | 03 December 2012 |
| Creators | Hyter, Stephen D. |
| Contributors | Indra, Arup |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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