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Regulation of gene expression in ovarian cancer cells by luteinizing hormone receptor expression and activation.

Cui J, Miner BM, Eldredge JB, Warrenfeltz SW, Dam P, Xu Y, Puett D - BMC Cancer (2011)

Bottom Line: Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses.Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors.The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.

ABSTRACT

Background: Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH) receptor (LHR) expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE) carcinoma cells.

Methods: The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours). Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses.

Results: Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are potential therapeutic targets, may reflect a positive mediation of ovarian cancer growth.

Conclusion: Overall, the present study elucidates the extensive transcriptomic changes of ovarian cancer cells in response to LH receptor activation, which provides a comprehensive and objective assessment for determining new cancer therapies and potential serum markers, of which over 100 are suggested.

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Distributions of the 2,373 differentially expressed genes in SKOV-3 cells across IPA functional families. Each blue bar represents the percentage of differentially expressed genes associated with LHR expression; each yellow bar represents the percentage of differentially expressed genes upon incubation with LH; each red bar is the percentage of all human genes. The x-axis represents the percentage and the y-axis denotes functional families.
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Figure 1: Distributions of the 2,373 differentially expressed genes in SKOV-3 cells across IPA functional families. Each blue bar represents the percentage of differentially expressed genes associated with LHR expression; each yellow bar represents the percentage of differentially expressed genes upon incubation with LH; each red bar is the percentage of all human genes. The x-axis represents the percentage and the y-axis denotes functional families.

Mentions: A total of 54,671 transcripts were originally profiled, among which 2,373 genes exhibited at least 2-fold differential expression between any two experimental groups (see detailed statistics in Additional file 1 Table S2), including 1,783 genes differentially expressed in LH-treated cells. Out of the 23 differentially expressed genes analyzed by qRT-PCR in this study and earlier [20], we found that 22 genes exhibit consistent expression pattern between microarray and qRT-PCR data (Additional file 1 Table S1), which indicate that majority differential information derived from microarray is reliable. According to the IPA annotation [27], 689 differential genes are cancer-related, and 265 genes are highly expressed in the ovary (see Additional file 1 Table S3). Five major functional families were found to be significantly enriched by the differentially expressed genes, including growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors (Figure 1). Generally, these differentially expressed genes participate in pathways involved in the cell cycle, focal adhesion, cytokine-cytokine receptor interaction, regulation of the actin cytoskeleton, purine metabolism, and a number of key signaling pathways such as MAPK, TGF-β, p53, and Jak-STAT.


Regulation of gene expression in ovarian cancer cells by luteinizing hormone receptor expression and activation.

Cui J, Miner BM, Eldredge JB, Warrenfeltz SW, Dam P, Xu Y, Puett D - BMC Cancer (2011)

Distributions of the 2,373 differentially expressed genes in SKOV-3 cells across IPA functional families. Each blue bar represents the percentage of differentially expressed genes associated with LHR expression; each yellow bar represents the percentage of differentially expressed genes upon incubation with LH; each red bar is the percentage of all human genes. The x-axis represents the percentage and the y-axis denotes functional families.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3141782&req=5

Figure 1: Distributions of the 2,373 differentially expressed genes in SKOV-3 cells across IPA functional families. Each blue bar represents the percentage of differentially expressed genes associated with LHR expression; each yellow bar represents the percentage of differentially expressed genes upon incubation with LH; each red bar is the percentage of all human genes. The x-axis represents the percentage and the y-axis denotes functional families.
Mentions: A total of 54,671 transcripts were originally profiled, among which 2,373 genes exhibited at least 2-fold differential expression between any two experimental groups (see detailed statistics in Additional file 1 Table S2), including 1,783 genes differentially expressed in LH-treated cells. Out of the 23 differentially expressed genes analyzed by qRT-PCR in this study and earlier [20], we found that 22 genes exhibit consistent expression pattern between microarray and qRT-PCR data (Additional file 1 Table S1), which indicate that majority differential information derived from microarray is reliable. According to the IPA annotation [27], 689 differential genes are cancer-related, and 265 genes are highly expressed in the ovary (see Additional file 1 Table S3). Five major functional families were found to be significantly enriched by the differentially expressed genes, including growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors (Figure 1). Generally, these differentially expressed genes participate in pathways involved in the cell cycle, focal adhesion, cytokine-cytokine receptor interaction, regulation of the actin cytoskeleton, purine metabolism, and a number of key signaling pathways such as MAPK, TGF-β, p53, and Jak-STAT.

Bottom Line: Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses.Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors.The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.

ABSTRACT

Background: Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH) receptor (LHR) expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE) carcinoma cells.

Methods: The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours). Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses.

Results: Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are potential therapeutic targets, may reflect a positive mediation of ovarian cancer growth.

Conclusion: Overall, the present study elucidates the extensive transcriptomic changes of ovarian cancer cells in response to LH receptor activation, which provides a comprehensive and objective assessment for determining new cancer therapies and potential serum markers, of which over 100 are suggested.

Show MeSH
Related in: MedlinePlus