Graduate Thesis Or Dissertation

 

Role of Melanocytic Vitamin D Receptor (VDR) in UVB-induced Melanocyte Homeostasisand Keratinocytic Retinoid–X-Receptor α (RXRα) in UVB Induced Melanomagenesis Public Deposited

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/bz60d1978

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  • Cutaneous melanoma remains the deadliest form of skin cancer arising from malignant transformation of pigment-producing melanocytes, 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. This DNA damage if incorrectly repaired, can result in incorporation of mutations that cause aberrant cell cycling and/or other functional defects that promote tumorigenesis. Melanoma incidence is on the rise throughout the U.S and thus a better understanding of the molecular mechanisms underlying its formation and progression are needed for the purpose of diagnosis and therapeutic targeting. Previous studies in humans have determined that there is an inverse correlation between Vitamin D Receptor (VDR) expression and melanoma progression, and loss of VDR enhances susceptibility to UV induced epithelial tumor formation in mice. To better understand the relationship between VDR loss and melanoma susceptibility, we have developed a mouse model where VDR is selectively deleted in melanocytes, the cells that transform into melanomas, to determine its role in melanocyte homeostasis and UV-induced DNA damage. In vivo ablation of VDR in melanocytes (Vdr[superscript mel-/-] mice), reduced the percentage of melanocyte precursors and mature differentiated melanocytes, as well as proliferating melanocyte, both pre- and post-UVB irradiation. VDR ablation significantly increased the proportion of UV induced DNA damaged melanocytes in the Vdr[superscript mel-/-] mice. Topical application of vitamin D3, inhibited UV induced DNA damage of melanocytes in the presence of functional VDR and this inhibition was abrogated in the absence of melanocytic VDR. Vdr[superscript mel-/-] mice also exhibited a reduction in melanocyte apoptosis after UVB exposure. Altogether, these results suggest that VDR plays an important role in controlling UV-induced DNA damage and melanocyte homeostasis in-vivo, and the protective effects of Vitamin D3 against the UV-induced DNA damage is mediated by functional VDR. Our previous studies have shown that mice selectively lacking the nuclear hormone receptor Retinoid X Receptor α, a heterodimeric partner of VDR, 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 signaling during melanoma progression. In the present study, we have generated a mouse model to establish the role for RXRα in spontaneous and acute UVB-induced melanocyte homeostasis and melanomagenesis. Combining Rxrαep-/-mice with activated CDK4 (R24C) and oncogenic NRAS (Q61K) mutations in a trigenic model [Rxrα[superscript ep-/-]| NRas[superscript Q61K]| CDK4[superscript R24C/R24C]] results in enhanced UVR-induced melanomagenesis compared to control mice. These melanomas show increased expression of markers of malignant progression, proliferation and tumor vascularization. Melanomas from trigenic mice display increased metastases of pigment-producing cells to draining lymph nodes. Interestingly, the tumor adjacent normal skin of these mice have reduced expression of pro-apoptotic Bax and upregulation of cyclin D1 and p21 in the presence and absence of UVB treatment suggesting that these changes are primarily driven by loss of keratinocytic RXRα in the tumor microenvironment. These, effects were exacerbated after exposure to a single neonatal UVB treatment and we observed additional activation of AKT and reduction in expression of pro-Caspase 3, suggesting that these changes are likely UV effects in combination with loss of RXRα protein in the keratinocytes. Besides enhancing melanomagenesis, keratinocytic RXRα loss results in a microenvironment favorable to primary tumor formation. Therefore, VDR in melanocytes has a “cell-autonomous” role to protect against UVB induced DNA damage and a pivotal role to control melanocyte homeostasis in vivo, while RXRα in keratinocytes modulate post-UVB survival of melanocytes in a “non-cell autonomous” manner. Altogether these results establish a multitude of roles for type II nuclear receptors in melanocyte homeostasis and melanomagenesis, and identifies them as potential targets for melanoma diagnosis and therapeutics.
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  • description.provenance : Approved for entry into archive by Julie Kurtz(julie.kurtz@oregonstate.edu) on 2016-11-16T17:22:51Z (GMT) No. of bitstreams: 2ChaganiSharmeenE2016.pdf: 3107595 bytes, checksum: c2ffd073f311cdb82dce1122d0de37bb (MD5)license_rdf: 1232 bytes, checksum: bb87e2fb4674c76d0d2e9ed07fbb9c86 (MD5)
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  • description.provenance : Made available in DSpace on 2016-11-16T20:36:14Z (GMT). No. of bitstreams: 2ChaganiSharmeenE2016.pdf: 3107595 bytes, checksum: c2ffd073f311cdb82dce1122d0de37bb (MD5)license_rdf: 1232 bytes, checksum: bb87e2fb4674c76d0d2e9ed07fbb9c86 (MD5) Previous issue date: 2016-10-04
  • description.provenance : Submitted by Sharmeen Chagani (chaganis@oregonstate.edu) on 2016-11-09T20:27:53ZNo. of bitstreams: 3license_rdf: 1232 bytes, checksum: bb87e2fb4674c76d0d2e9ed07fbb9c86 (MD5)ChaganiSharmeenE2016.pdf: 3107083 bytes, checksum: 6199f71d2d9fe78dfd2dfcf95c429c1a (MD5)embargo form.pdf: 258533 bytes, checksum: dad370a868a44b8fb43e6f36e551faca (MD5)
  • description.provenance : Submitted by Sharmeen Chagani (chaganis@oregonstate.edu) on 2016-11-15T22:12:36ZNo. of bitstreams: 2ChaganiSharmeenE2016.pdf: 3107595 bytes, checksum: c2ffd073f311cdb82dce1122d0de37bb (MD5)license_rdf: 1232 bytes, checksum: bb87e2fb4674c76d0d2e9ed07fbb9c86 (MD5)
  • description.provenance : Rejected by Julie Kurtz(julie.kurtz@oregonstate.edu), reason: Hi Sharmeen,Rejecting for the following reasons -1) Remove the bold print on the title page, in the heading and word "Title:"2) Title page - add on the bottom - Commencement June 20173) Table of Contents subheading - Page, change to 12pt font and move to next line down so it's not on the same line as the heading. Do this also for the List of Figures and List of Tables subheadings.4) Remove the file name "Embargo Form". This goes in your file and is not uploaded to ScholarsArchive.Everything else looks good. Once revised, log back into ScholarsArchive and go to the upload page. Replace the attached files with the revised PDF and resubmit.Thanks,Julie on 2016-11-15T19:19:37Z (GMT)
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  • 2017-11-06 to 2018-02-13

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