A Subset of Nuclear Receptors Are Uniquely Expressed in Uveal Melanoma Cells
Uveal melanoma (UM) is recognized as the most common intraocular malignancy and the second most common form of melanoma. Nearly 50% of UM patients develop untreatable and fatal metastases. The 48-member nuclear receptor (NR) superfamily represents a therapeutically targetable group of transcriptio...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2015-07-01
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| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fendo.2015.00093/full |
| _version_ | 1811277157511462912 |
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| author | Kenneth Edward Huffman Ryan eCarstens Elisabeth D Martinez Elisabeth D Martinez |
| author_facet | Kenneth Edward Huffman Ryan eCarstens Elisabeth D Martinez Elisabeth D Martinez |
| author_sort | Kenneth Edward Huffman |
| collection | DOAJ |
| description | Uveal melanoma (UM) is recognized as the most common intraocular malignancy and the second most common form of melanoma. Nearly 50% of UM patients develop untreatable and fatal metastases. The 48-member nuclear receptor (NR) superfamily represents a therapeutically targetable group of transcription factors known for their regulation of key cancer pathways in numerous tumor types. Here, we profiled the expression of the 48 human NRs by qRT-PCR across a melanoma cell line panel including five UM lines, nine cutaneous melanoma (CM) lines, and normal primary melanocytes. NR expression patterns identified a few key features. First, in agreement with our past studies identifying RXRg as a CM-specific marker, we found that UM cells also exhibit high levels of RXRg expression, making it a universal biomarker for melanoma tumors. Second, we found that LXRb is highly expressed in both UM and CM lines, suggesting that it may be a therapeutic target in a UM metastatic setting as it has been in CM models. Third, we found that RARg, PPARd, EAR2, RXRa, and TRa expression could subdivide UM from CM. Previous studies of UM cancers identified key mutations in three genes: GNAQ, GNA11, and BRAF. We found unique NR expression profiles associated with each of these UM mutations. We then performed NR-to-NR and NR-to-genome expression correlation analysis to find potential NR-driven transcriptional programs activated in UM and CM. Specifically, RXRg controlled gene networks were identified that may drive melanoma-specific signaling and metabolism. ERRa was identified as a UM-defining NR and genes correlated with its expression confirm the role of ERRa in metabolic control. Given the plethora of available NR agonists, antagonists, and selective receptor modulators, pharmacologic manipulation of these NRs and their transcriptional outputs may lead to a more comprehensive understanding of key UM pathways and how we can leverage them for better therapeutic alternatives. |
| first_indexed | 2024-04-13T00:11:48Z |
| format | Article |
| id | doaj.art-d8d00ead2aa14fb788a00e37756405a9 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-13T00:11:48Z |
| publishDate | 2015-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-d8d00ead2aa14fb788a00e37756405a92022-12-22T03:11:05ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922015-07-01610.3389/fendo.2015.00093146023A Subset of Nuclear Receptors Are Uniquely Expressed in Uveal Melanoma CellsKenneth Edward Huffman0Ryan eCarstens1Elisabeth D Martinez2Elisabeth D Martinez3UT Southwestern Medical CenterUT Southwestern Medical CenterUT Southwestern Medical CenterUT Southwestern Medical CenterUveal melanoma (UM) is recognized as the most common intraocular malignancy and the second most common form of melanoma. Nearly 50% of UM patients develop untreatable and fatal metastases. The 48-member nuclear receptor (NR) superfamily represents a therapeutically targetable group of transcription factors known for their regulation of key cancer pathways in numerous tumor types. Here, we profiled the expression of the 48 human NRs by qRT-PCR across a melanoma cell line panel including five UM lines, nine cutaneous melanoma (CM) lines, and normal primary melanocytes. NR expression patterns identified a few key features. First, in agreement with our past studies identifying RXRg as a CM-specific marker, we found that UM cells also exhibit high levels of RXRg expression, making it a universal biomarker for melanoma tumors. Second, we found that LXRb is highly expressed in both UM and CM lines, suggesting that it may be a therapeutic target in a UM metastatic setting as it has been in CM models. Third, we found that RARg, PPARd, EAR2, RXRa, and TRa expression could subdivide UM from CM. Previous studies of UM cancers identified key mutations in three genes: GNAQ, GNA11, and BRAF. We found unique NR expression profiles associated with each of these UM mutations. We then performed NR-to-NR and NR-to-genome expression correlation analysis to find potential NR-driven transcriptional programs activated in UM and CM. Specifically, RXRg controlled gene networks were identified that may drive melanoma-specific signaling and metabolism. ERRa was identified as a UM-defining NR and genes correlated with its expression confirm the role of ERRa in metabolic control. Given the plethora of available NR agonists, antagonists, and selective receptor modulators, pharmacologic manipulation of these NRs and their transcriptional outputs may lead to a more comprehensive understanding of key UM pathways and how we can leverage them for better therapeutic alternatives.http://journal.frontiersin.org/Journal/10.3389/fendo.2015.00093/fullUveal Melanomacutaneous melanomaprofilingNCI-60Nuclear receptor expression |
| spellingShingle | Kenneth Edward Huffman Ryan eCarstens Elisabeth D Martinez Elisabeth D Martinez A Subset of Nuclear Receptors Are Uniquely Expressed in Uveal Melanoma Cells Frontiers in Endocrinology Uveal Melanoma cutaneous melanoma profiling NCI-60 Nuclear receptor expression |
| title | A Subset of Nuclear Receptors Are Uniquely Expressed in Uveal Melanoma Cells |
| title_full | A Subset of Nuclear Receptors Are Uniquely Expressed in Uveal Melanoma Cells |
| title_fullStr | A Subset of Nuclear Receptors Are Uniquely Expressed in Uveal Melanoma Cells |
| title_full_unstemmed | A Subset of Nuclear Receptors Are Uniquely Expressed in Uveal Melanoma Cells |
| title_short | A Subset of Nuclear Receptors Are Uniquely Expressed in Uveal Melanoma Cells |
| title_sort | subset of nuclear receptors are uniquely expressed in uveal melanoma cells |
| topic | Uveal Melanoma cutaneous melanoma profiling NCI-60 Nuclear receptor expression |
| url | http://journal.frontiersin.org/Journal/10.3389/fendo.2015.00093/full |
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