Genome-wide transcriptional regulation of estrogen receptor targets in fallopian tube cells and the role of selective estrogen receptor modulators.
Genome-wide transcriptional regulation of estrogen receptor targets in fallopian tube cells and the role of selective estrogen receptor modulators.
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DOI：
10.1186/s13048-016-0213-3
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发表时间：
2016-02-15
影响因子：
4
通讯作者：
Burdette JE
中科院分区：
文献类型：
--
作者：
Moyle-Heyrman G;Schipma MJ;Dean M;Davis DA;Burdette JE
输卵管上皮是高级浆液性卵巢癌（HGSC）的潜在来源之一。使用雌激素替代疗法增加卵巢癌（OVCA）的风险。尽管雌激素对OVCA有影响，但选择性雌激素受体调节剂（SERMs）通常只有20%的应答率。这种低反应可能是由于多种因素，包括雌激素受体信号的丢失或雌激素在不同潜在细胞类型起源中的作用。输卵管上皮对SERMs的反应尚不清楚，这将有助于确定这种细胞类型（如HGSC）引起的肿瘤的治疗方案。利用正常小鼠衍生的输卵管上皮细胞（小鼠相当于输卵管）证实了雌激素受体的表达，并与其配体雌二醇相互作用，触发孕激素受体（PR） mRNA和蛋白的诱导。SERMs 4-羟他莫昔芬、雷洛昔芬和去甲基拉唑昔芬在输卵管细胞中作为雌激素受体拮抗剂起作用。细胞增殖和迁移实验表明雌二醇对细胞迁移和增殖没有显著影响。进一步，利用RNAseq，确定并验证了雌激素受体在雌二醇和4-羟他莫昔芬信号刺激下的输卵管特异性转录基因靶点。RNA-seq显示在增殖、抗凋亡、钙信号和类固醇信号过程中富集。最后，我们研究了一组HGSC细胞系的ER和PR受体状态，包括Kuramochi、OVSAHO、OVKATE、OVCAR3和OVCAR4。OVSAHO显示了受体的表达和反应，这突出了对雌激素反应的卵巢癌的其他模型的需求。综上所述，输卵管具有雌激素受体的特异性基因靶点，并对SERMs表现出与拮抗作用一致的组织特异性反应。本文的在线版本（doi:10.1186/s13048-016-0213-3）包含补充材料，仅供授权用户使用。
The fallopian tube epithelium is one of the potential sources of high-grade serous ovarian cancer (HGSC). The use of estrogen only hormone replacement therapy increases ovarian cancer (OVCA) risk. Despite estrogen’s influence in OVCA, selective estrogen receptor modulators (SERMs) typically demonstrate only a 20 % response rate. This low response could be due to a variety of factors including the loss of estrogen receptor signaling or the role of estrogen in different potential cell types of origin. The response of fallopian tube epithelium to SERMs is not known, and would be useful when determining therapeutic options for tumors arising from this cell type, such as HGSC. Using normal murine derived oviductal epithelial cells (mouse equivalent to the fallopian tube) estrogen receptor expression was confirmed and interaction with its ligand, estradiol, triggered mRNA and protein induction of progesterone receptor (PR). The SERMs 4-hydroxytamoxifen, raloxifene and desmethylarzoxifene, functioned as estrogen receptor antagonists in oviductal cells. Cellular proliferation and migration assays suggested that estradiol does not significantly impact cellular migration and increased proliferation. Further, using RNAseq, the oviduct specific transcriptional genes targets of ER when stimulated by estradiol and 4-hydroxytamoxifen signaling were determined and validated. The RNA-seq revealed enrichment in proliferation, anti-apoptosis, calcium signaling and steroid signaling processes. Finally, the ER and PR receptor status of a panel of HGSC cell lines was investigated including Kuramochi, OVSAHO, OVKATE, OVCAR3, and OVCAR4. OVSAHO demonstrated receptor expression and response, which highlights the need for additional models of ovarian cancer that are estrogen responsive. Overall, the fallopian tube has specific gene targets of estrogen receptor and demonstrates a tissue specific response to SERMs consistent with antagonistic action. The online version of this article (doi:10.1186/s13048-016-0213-3) contains supplementary material, which is available to authorized users.