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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

Nuclear receptor expression in melanomas. Clustered heat map representation of mRNA expression levels of the 48 human NRs in a panel of human uveal melanoma (n = 5) and cutaneous melanoma (n = 9) cell lines as measured by qRT-PCR. Additionally, a melanocyte was included as a normal comparator. Unsupervised hierarchical clustering (Distance calculations: Manhattan, Aggregation method: Ward’s) was performed on the NRs (columns) and cell line samples (rows, colored according to key). qRT-PCR data were quantified using standard curves and normalized to 18S as described in Section “Materials and Methods.” Data are color coded such that relatively highly expressed NRs are dark blue while lowly or unexpressed receptors (cycle time >35) are white.
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Figure 1: Nuclear receptor expression in melanomas. Clustered heat map representation of mRNA expression levels of the 48 human NRs in a panel of human uveal melanoma (n = 5) and cutaneous melanoma (n = 9) cell lines as measured by qRT-PCR. Additionally, a melanocyte was included as a normal comparator. Unsupervised hierarchical clustering (Distance calculations: Manhattan, Aggregation method: Ward’s) was performed on the NRs (columns) and cell line samples (rows, colored according to key). qRT-PCR data were quantified using standard curves and normalized to 18S as described in Section “Materials and Methods.” Data are color coded such that relatively highly expressed NRs are dark blue while lowly or unexpressed receptors (cycle time >35) are white.

Mentions: To investigate the expression levels of the human NR superfamily (n = 48) in UM, we performed high-throughput qRT-PCR expression analysis across a cell line panel consisting of five UM cell lines, nine CM cell lines from the NCI-60 (27), and one primary melanocyte control (Figure 1). A heat map was generated to display the results and it was seen that several receptors including SF-1, SHP, TLX, PR, and HNF4a are either expressed at very low levels or completely unexpressed across the panel, suggesting that they do not play a large role in either CM or UM. Other receptors, such as COUPT-FII, LXRb, and RXRg, were found to be strongly expressed across all the samples analyzed. GR, NOR1, NURR1, PPARa, TR2, and TR4 were also expressed in all samples, but at more moderate levels.


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

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

Nuclear receptor expression in melanomas. Clustered heat map representation of mRNA expression levels of the 48 human NRs in a panel of human uveal melanoma (n = 5) and cutaneous melanoma (n = 9) cell lines as measured by qRT-PCR. Additionally, a melanocyte was included as a normal comparator. Unsupervised hierarchical clustering (Distance calculations: Manhattan, Aggregation method: Ward’s) was performed on the NRs (columns) and cell line samples (rows, colored according to key). qRT-PCR data were quantified using standard curves and normalized to 18S as described in Section “Materials and Methods.” Data are color coded such that relatively highly expressed NRs are dark blue while lowly or unexpressed receptors (cycle time >35) are white.
© Copyright Policy
Related In: Results  -  Collection

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Figure 1: Nuclear receptor expression in melanomas. Clustered heat map representation of mRNA expression levels of the 48 human NRs in a panel of human uveal melanoma (n = 5) and cutaneous melanoma (n = 9) cell lines as measured by qRT-PCR. Additionally, a melanocyte was included as a normal comparator. Unsupervised hierarchical clustering (Distance calculations: Manhattan, Aggregation method: Ward’s) was performed on the NRs (columns) and cell line samples (rows, colored according to key). qRT-PCR data were quantified using standard curves and normalized to 18S as described in Section “Materials and Methods.” Data are color coded such that relatively highly expressed NRs are dark blue while lowly or unexpressed receptors (cycle time >35) are white.
Mentions: To investigate the expression levels of the human NR superfamily (n = 48) in UM, we performed high-throughput qRT-PCR expression analysis across a cell line panel consisting of five UM cell lines, nine CM cell lines from the NCI-60 (27), and one primary melanocyte control (Figure 1). A heat map was generated to display the results and it was seen that several receptors including SF-1, SHP, TLX, PR, and HNF4a are either expressed at very low levels or completely unexpressed across the panel, suggesting that they do not play a large role in either CM or UM. Other receptors, such as COUPT-FII, LXRb, and RXRg, were found to be strongly expressed across all the samples analyzed. GR, NOR1, NURR1, PPARa, TR2, and TR4 were also expressed in all samples, but at more moderate levels.

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