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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

Identification of NR expression patterns within uveal melanoma subtypes. (A) Comparisons were made between replicate data generated from UM cell line pair OMM2.3 (metastasis-derived) and MEL270 (primary-derived) with p-values calculated through a Bonferroni-corrected Student’s t-test. ERa and GR expressions were lost in the metastatic line (top) while LXRb and PPARg expressions were higher in the metastasis (bottom). (B) NGFIB expression was found higher in the metastasis-derived UM cell lines versus the primary-derived UM lines (p-value from corrected t-test). (C) Receptor expression was compared between the different mutational states of UM. (Top) NOR1 was found overexpressed in the GNA11 mutant, (middle) AR expression was retained in the BRAF mutants, and (bottom) RORa expression was lost in the GNAQ mutant cell lines.
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Figure 4: Identification of NR expression patterns within uveal melanoma subtypes. (A) Comparisons were made between replicate data generated from UM cell line pair OMM2.3 (metastasis-derived) and MEL270 (primary-derived) with p-values calculated through a Bonferroni-corrected Student’s t-test. ERa and GR expressions were lost in the metastatic line (top) while LXRb and PPARg expressions were higher in the metastasis (bottom). (B) NGFIB expression was found higher in the metastasis-derived UM cell lines versus the primary-derived UM lines (p-value from corrected t-test). (C) Receptor expression was compared between the different mutational states of UM. (Top) NOR1 was found overexpressed in the GNA11 mutant, (middle) AR expression was retained in the BRAF mutants, and (bottom) RORa expression was lost in the GNAQ mutant cell lines.

Mentions: Finally, we compared NR profiles across the different UM cell lines (Figure 4). Because UM metastatic disease is essentially fatal, we were particularly interested in identifying metastasis-specific NR expression patterns. Initially, we chose to compare NR expression in the cell line pair MEL270 (primary) and OMM2.3 (metastasis), both of which were derived from the same patient. Several genes were found differentially expressed between the pair with the most significant, liganded NRs highlighted in Figure 4A. ERa and GR expressions were found to be lost in the metastasis-derived OMM2.3 versus the primary MEL270. Conversely, LXRb and PPARg expressions were either significantly lower (LXRb) or completely undetected (PPARg) in the primary while robust expression was seen in the metastatic line, suggesting that these genes were up-regulated during the metastatic process and may be essential for retention of proliferative capacity or for survival at distant anatomical sites.


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

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

Identification of NR expression patterns within uveal melanoma subtypes. (A) Comparisons were made between replicate data generated from UM cell line pair OMM2.3 (metastasis-derived) and MEL270 (primary-derived) with p-values calculated through a Bonferroni-corrected Student’s t-test. ERa and GR expressions were lost in the metastatic line (top) while LXRb and PPARg expressions were higher in the metastasis (bottom). (B) NGFIB expression was found higher in the metastasis-derived UM cell lines versus the primary-derived UM lines (p-value from corrected t-test). (C) Receptor expression was compared between the different mutational states of UM. (Top) NOR1 was found overexpressed in the GNA11 mutant, (middle) AR expression was retained in the BRAF mutants, and (bottom) RORa expression was lost in the GNAQ mutant cell lines.
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Figure 4: Identification of NR expression patterns within uveal melanoma subtypes. (A) Comparisons were made between replicate data generated from UM cell line pair OMM2.3 (metastasis-derived) and MEL270 (primary-derived) with p-values calculated through a Bonferroni-corrected Student’s t-test. ERa and GR expressions were lost in the metastatic line (top) while LXRb and PPARg expressions were higher in the metastasis (bottom). (B) NGFIB expression was found higher in the metastasis-derived UM cell lines versus the primary-derived UM lines (p-value from corrected t-test). (C) Receptor expression was compared between the different mutational states of UM. (Top) NOR1 was found overexpressed in the GNA11 mutant, (middle) AR expression was retained in the BRAF mutants, and (bottom) RORa expression was lost in the GNAQ mutant cell lines.
Mentions: Finally, we compared NR profiles across the different UM cell lines (Figure 4). Because UM metastatic disease is essentially fatal, we were particularly interested in identifying metastasis-specific NR expression patterns. Initially, we chose to compare NR expression in the cell line pair MEL270 (primary) and OMM2.3 (metastasis), both of which were derived from the same patient. Several genes were found differentially expressed between the pair with the most significant, liganded NRs highlighted in Figure 4A. ERa and GR expressions were found to be lost in the metastasis-derived OMM2.3 versus the primary MEL270. Conversely, LXRb and PPARg expressions were either significantly lower (LXRb) or completely undetected (PPARg) in the primary while robust expression was seen in the metastatic line, suggesting that these genes were up-regulated during the metastatic process and may be essential for retention of proliferative capacity or for survival at distant anatomical sites.

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