Differential induction of LRP16 by liganded and unliganded estrogen receptor alpha in SKOV3 ovarian carcinoma cells.
Differential induction of LRP16 by liganded and unliganded estrogen receptor alpha in SKOV3 ovarian carcinoma cells.
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DOI：
10.1677/joe-09-0054
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发表时间：
2009-07
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影响因子：
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通讯作者：
L. Tian;Zhiqiang Wu;Ya-li Zhao;Y. Meng;Y. Si;Xiaobing Fu;Y. Mu;W. Han
中科院分区：
文献类型：
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作者：
L. Tian;Zhiqiang Wu;Ya-li Zhao;Y. Meng;Y. Si;Xiaobing Fu;Y. Mu;W. Han
以前，我们研究了雌激素（17 β-雌二醇，E（2））对LRP 16表达的诱导作用，并建立了一种前馈机制，激活雌激素依赖性上皮癌细胞中的雌激素受体α（ER α）反式激活。LRP 16通过作为ER α共激活剂发挥作用而为ER α信号转导所需。在这项研究中，我们证明了LRP 16的表达在E（2）反应性BG-1卵巢癌细胞中上调，但在雌激素耐药的SKOV 3卵巢癌细胞中下调。纯雌激素拮抗剂ICI 182 780对SKOV 3细胞LRP 16表达无影响。在SKOV 3细胞中，未配体的ER α上调LRP 16表达并增强LRP 16启动子活性;然而，这种诱导被雌激素刺激阻断。染色质免疫沉淀实验的结果显示，在没有雌激素的情况下，LRP 16启动子处的未配体ER α被强烈募集;然而，在E（2）刺激下，ER α大部分从DNA中释放。LRP 16表达水平的调节没有显著改变SKOV 3细胞的增殖率和细胞对E的生长反应性（2）。在SKOV 3细胞中通过RNA干扰敲低LRP 16显著减弱了雌激素反应元件依赖的ER α报告基因活性和E（2）诱导的c-Myc表达。我们的研究提示卵巢癌雌激素抵抗的一种新机制，即雌激素抑制的信号通路拮抗雌激素激活的信号转导。
Previously, we investigated the induction effect of LRP16 expression by estrogen (17beta-estradiol, E(2)) and established a feed-forward mechanism that activated estrogen receptor alpha (ERalpha) transactivation in estrogen-dependent epithelial cancer cells. LRP16 is required for ERalpha signaling transduction by functioning as an ERalpha coactivator. In this study, we demonstrated that LRP16 expression was upregulated in E(2)-responsive BG-1 ovarian cancer cells, but was downregulated in estrogen-resistant SKOV3 ovarian cancer cells. Pure estrogen antagonist ICI 182 780 did not affect LRP16 expression in SKOV3 cell. The unliganded ERalpha upregulated LRP16 expression and enhanced LRP16 promoter activity in SKOV3 cells; however, this induction was blocked by estrogen stimulation. Results from chromatin immunoprecipitation experiment revealed a strong recruitment of the unliganded ERalpha at LRP16 promoter in the absence of estrogen; however, ERalpha was largely released from the DNA upon E(2) stimulation. Modulation in LRP16 expression level did not significantly change the proliferation rate of SKOV3 cells and the growth responsiveness of cells to E(2). Knockdown of LRP16 by RNA interference in SKOV3 cells markedly attenuated estrogen response element-dependent ERalpha reporter gene activity and E(2)-induced c-Myc expression. Our study suggests a novel mechanism of estrogen resistance of ovarian cancer by which estrogen-repressed signaling pathway antagonizes estrogen-activated signaling transduction.