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A Subset of Nuclear Receptors are Uniquely Expressed in Uveal Melanoma Cells.

Huffman KE, Carstens R, Martinez ED - Front Endocrinol (Lausanne) (2015)

Bottom Line: 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 expressions could subdivide UM from CM.We found unique NR expression profiles associated with each of these UM mutations.

View Article: PubMed Central - PubMed

Affiliation: Hamon Center for Therapeutic Oncology Research , Dallas, TX , USA.

ABSTRACT
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 5 UM lines, 9 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 expressions 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 analyses 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.

No MeSH data available.


Related in: MedlinePlus

Uveal versus cutaneous melanoma NR expression patterns. Patterns of mRNA expression across the cell line panel for select receptors. p-Values are shown for the comparison of the expression level of the indicated nuclear receptor between uveal and cutaneous melanoma cell lines. Calculations were performed using a Student’s t-test and were Bonferroni-corrected for to account for multiple-hypothesis testing. (A) Three receptors (RARg, PPARd, and EAR2) are lost in cutaneous melanoma but retained in the uveal melanoma samples (versus melanocyte expression). (B) (Top) RXRa is lost in uveal melanoma samples. (Middle) TRa is overexpressed by cutaneous melanomas. (Bottom) LXRb expression is higher in uveal melanoma samples.
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Figure 2: Uveal versus cutaneous melanoma NR expression patterns. Patterns of mRNA expression across the cell line panel for select receptors. p-Values are shown for the comparison of the expression level of the indicated nuclear receptor between uveal and cutaneous melanoma cell lines. Calculations were performed using a Student’s t-test and were Bonferroni-corrected for to account for multiple-hypothesis testing. (A) Three receptors (RARg, PPARd, and EAR2) are lost in cutaneous melanoma but retained in the uveal melanoma samples (versus melanocyte expression). (B) (Top) RXRa is lost in uveal melanoma samples. (Middle) TRa is overexpressed by cutaneous melanomas. (Bottom) LXRb expression is higher in uveal melanoma samples.

Mentions: We next examined NRs differentially expressed between UM and CM (Figure 2). First, three NRs (RARg, PPARd, and EAR2) were found to have significantly lower expression levels in CM than in UM cell lines. Comparison to the melanocyte control suggested that the UM samples had retained “normal” expression of these receptors while expression had been lost in the CM samples. Conversely, it was found that RXRa expression was lower in UM than in CM or in the melanocyte control, suggesting UM had specifically lost RXRa expression. Analysis of TRa levels found that UM lines retained expression of this NR similar to that of the melanocyte, but that expression of TRa was significantly higher in CM. By contrast, REVerb an expression appears to be lost specifically in UM. As was previously mentioned, LXRb is highly expressed across all melanoma samples, but is expressed significantly higher in UM samples. This finding is particularly notable since LXRb agonists have been shown to reduce proliferative and metastatic potential in CM pre-clinical mouse models (28).


A Subset of Nuclear Receptors are Uniquely Expressed in Uveal Melanoma Cells.

Huffman KE, Carstens R, Martinez ED - Front Endocrinol (Lausanne) (2015)

Uveal versus cutaneous melanoma NR expression patterns. Patterns of mRNA expression across the cell line panel for select receptors. p-Values are shown for the comparison of the expression level of the indicated nuclear receptor between uveal and cutaneous melanoma cell lines. Calculations were performed using a Student’s t-test and were Bonferroni-corrected for to account for multiple-hypothesis testing. (A) Three receptors (RARg, PPARd, and EAR2) are lost in cutaneous melanoma but retained in the uveal melanoma samples (versus melanocyte expression). (B) (Top) RXRa is lost in uveal melanoma samples. (Middle) TRa is overexpressed by cutaneous melanomas. (Bottom) LXRb expression is higher in uveal melanoma samples.
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Figure 2: Uveal versus cutaneous melanoma NR expression patterns. Patterns of mRNA expression across the cell line panel for select receptors. p-Values are shown for the comparison of the expression level of the indicated nuclear receptor between uveal and cutaneous melanoma cell lines. Calculations were performed using a Student’s t-test and were Bonferroni-corrected for to account for multiple-hypothesis testing. (A) Three receptors (RARg, PPARd, and EAR2) are lost in cutaneous melanoma but retained in the uveal melanoma samples (versus melanocyte expression). (B) (Top) RXRa is lost in uveal melanoma samples. (Middle) TRa is overexpressed by cutaneous melanomas. (Bottom) LXRb expression is higher in uveal melanoma samples.
Mentions: We next examined NRs differentially expressed between UM and CM (Figure 2). First, three NRs (RARg, PPARd, and EAR2) were found to have significantly lower expression levels in CM than in UM cell lines. Comparison to the melanocyte control suggested that the UM samples had retained “normal” expression of these receptors while expression had been lost in the CM samples. Conversely, it was found that RXRa expression was lower in UM than in CM or in the melanocyte control, suggesting UM had specifically lost RXRa expression. Analysis of TRa levels found that UM lines retained expression of this NR similar to that of the melanocyte, but that expression of TRa was significantly higher in CM. By contrast, REVerb an expression appears to be lost specifically in UM. As was previously mentioned, LXRb is highly expressed across all melanoma samples, but is expressed significantly higher in UM samples. This finding is particularly notable since LXRb agonists have been shown to reduce proliferative and metastatic potential in CM pre-clinical mouse models (28).

Bottom Line: 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 expressions could subdivide UM from CM.We found unique NR expression profiles associated with each of these UM mutations.

View Article: PubMed Central - PubMed

Affiliation: Hamon Center for Therapeutic Oncology Research , Dallas, TX , USA.

ABSTRACT
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 5 UM lines, 9 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 expressions 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 analyses 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.

No MeSH data available.


Related in: MedlinePlus