Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
BMC Cancer. 2011 Jun 28;11:280. doi: 10.1186/1471-2407-11-280.
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.
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.
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.
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.
由于相当大比例的卵巢癌表达促性腺激素受体，并在绝经后年份对垂体促性腺激素的相对高浓度有反应，因此有人提出受体激活可能有助于肿瘤的病因和/或进展。本研究的目的是开发一种细胞模型，以确定黄体生成素 (LH) 受体 (LHR) 表达和 LH 介导的 LHR 激活对基因表达的影响，从而深入了解促性腺激素对卵巢表面上皮 (OSE) 癌细胞作用的机制。
将人卵巢癌细胞系 SKOV-3 稳定转染以表达功能性 LHR，并与 LH 孵育不同时间（0-20 小时）。通过微阵列和 qRT-PCR 分析对这些细胞进行转录组谱分析，以确定 LHR 表达/激活依赖性基因表达水平和途径的变化。
通过对暴露于 LH 的 LHR 转染 SKOV-3 细胞的比较分析，我们观察到 1783 个基因对 LH 处理的差异表达，其中 5 个显著家族被富集，包括生长因子、翻译调节剂、转运蛋白、G 蛋白偶联受体和配体依赖性核受体。发现最早和中期诱导的基因高度表达占据了一个影响转录调节、细胞生长、凋亡和多种信号转导的网络，表明 LH 诱导的凋亡和细胞生长抑制通过例如肿瘤坏死因子、Jun 和许多其他因子的显著变化，支持在体外测定中观察到的细胞生长减少。然而，其他观察结果，例如编码内皮素-1 亚型 A 受体、基质细胞衍生因子 1 和胰岛素样生长因子 II 的基因的大量上调，所有这些都是潜在的治疗靶点，可能反映了卵巢癌生长的积极介导。
总体而言，本研究阐明了卵巢癌细胞对 LH 受体激活的广泛转录组变化，为确定新的癌症治疗方法和潜在的血清标志物提供了全面和客观的评估，其中建议了超过 100 个标志物。
