Abstract
BackgroundSince 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.MethodsThe 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.ResultsThrough 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.ConclusionOverall, 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.
Highlights
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
SKOV-3 Cells and Transfection The parent SKOV-3 ovarian cancer cell line was chosen as a control in this study since it does not express LH receptor (LHR) [14,19,20], and, following transfection, the LHR+ cells serve to determine the alterations in gene expression elicited by luteinizing hormone (LH)
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
Summary
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 relatively high death rate, compared to diagnosed cases, is due to the lack of an effective method for early detection. The cancer has progressed to an advanced stage when detected, with only about a fourth of the women having the disease correctly diagnosed in a localized state. Major factors, including inherited mutations in the BRCA1 and BRCA2 genes [3,4] and conditions that lead to more ovulatory periods, such as early menarche, late menopause, and nulliparity [5], have been strongly linked to increased risk of ovarian cancer development; the role of carcinogens and other possible contributing factors are still largely unknown [6]
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