Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, 111 TW Alexander Drive, Research Triangle Park, NC 27709, USA.
Horm Cancer. 2012 Jun;3(3):79-92. doi: 10.1007/s12672-012-0103-0.
Sex hormones and growth factors have been implicated in the pathogenesis of uterine leiomyomas. The uterus is also an abundant source of the glucocorticoid receptor but its role and function have been largely ignored. Human samples of uterine leiomyomas and matched myometrium retain expression of the glucocorticoid receptor (GR) suggesting a potential role for GR in leiomyoma function. However, hormone responsive gene expression varies between normal myometrium and leiomyoma cells. We now employ genome-wide microarray studies comparing glucocorticoid and estrogen-treated human uterine leiomyoma cells to those treated with both steroids to identify the potential role of glucocorticoids in uterine leiomyoma cells. Treatment with the synthetic glucocorticoid dexamethasone (Dex) regulated 3,128 probes. Estrogen (E(2)) treatment identified 2,094 probes, and in the presence of both hormones, 4,626 probes were regulated. Of the 552 probes identified, the majority of genes co-regulated by Dex, E(2), and Dex + E(2) exhibited co-downregulation. Interestingly, a small group of 17 genes displayed antagonistic regulation by Dex and E(2), where all genes in this group, Dex reversed the E(2) effect with. Ingenuity Pathway Analysis of the data identified cell growth, development, and differentiation as significant glucocorticoid regulated pathways. Flow cytometry confirmed that glucocorticoids regulated cell proliferation and significantly reduced the percentage of S-phase cells either in the presence or absence of estrogen in leiomyomas but not smooth muscle cells. Translation of our results suggest that glucocorticoids may play a significant role in regulating uterine leiomyoma gene expression and cell growth, and thus may have implications for therapeutic development of uterine leiomyoma treatment.
性激素和生长因子已被牵涉到子宫肌瘤的发病机制中。子宫也是糖皮质激素受体的丰富来源，但它的作用和功能在很大程度上被忽视了。人类子宫肌瘤和匹配的子宫肌组织样本保留了糖皮质激素受体（GR）的表达，这表明 GR 在子宫肌瘤功能中可能具有潜在作用。然而，激素反应基因表达在正常子宫肌和子宫肌瘤细胞之间存在差异。我们现在采用全基因组微阵列研究比较糖皮质激素和雌激素处理的人子宫肌瘤细胞与同时用两种类固醇处理的细胞，以确定糖皮质激素在子宫肌瘤细胞中的潜在作用。用合成糖皮质激素地塞米松（Dex）处理调节了 3128 个探针。雌激素（E2）处理鉴定出 2094 个探针，而在两种激素存在的情况下，调节了 4626 个探针。在鉴定出的 552 个探针中，大多数被 Dex、E2 和 Dex+E2 共同调节的基因表现出共同下调。有趣的是，一小群 17 个基因表现出 Dex 和 E2 的拮抗调节，其中该组中所有基因都被 Dex 逆转了 E2 的作用。对数据的 Ingenuity 通路分析确定细胞生长、发育和分化是显著受糖皮质激素调节的途径。流式细胞术证实，糖皮质激素调节细胞增殖，并显著降低了子宫肌瘤中存在或不存在雌激素时 S 期细胞的百分比，但对平滑肌细胞没有影响。我们研究结果的翻译表明，糖皮质激素可能在调节子宫肌瘤基因表达和细胞生长方面发挥重要作用，因此可能对子宫肌瘤治疗的治疗发展具有重要意义。
