Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer.
Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer.
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Linc-RoR促进MAPK/ERK信号传导并促进乳腺癌不依赖雌激素的生长。
DOI：
10.1186/s12943-017-0727-3
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发表时间：
2017-10-17
期刊：
影响因子：
37.3
通讯作者：
Mo YY
中科院分区：
文献类型：
--
作者：
Peng WX;Huang JG;Yang L;Gong AH;Mo YY
ER+乳腺癌细胞从雌激素依赖性状态向雌激素非依赖性状态的转变是促进对内分泌治疗耐药的关键步骤。虽然MAPK/ERK信号通路在雌激素非依赖性乳腺癌细胞生长中的关键作用已经得到了很好的证实，但其潜在的机制还不完全清楚。在这项研究中，我们针对从lncRNA数据库中选择的一组集中的lncRNA分析了lncRNA的表达。采用CRISPR/Cas9敲除（KO）MCF-7细胞中的linc-RoR，同时进行拯救实验以在KO细胞中重新表达linc-RoR。集落形成和MTT测定用于检查linc-RoR在雌激素非依赖性生长和他莫昔芬抗性中的作用。Western blot和qRT-PCR分别检测蛋白质和lncRNA水平的变化。从Oncomine（www.oncomine.org）下载临床样本中DUSP 7的表达，并使用来自Kaplan-Meier Plotter（http：//www.example.com）的数据集分析与DUSP 7相关的临床结果。kmplot.com我们确定linc-RoR作为癌-lncRNA发挥作用，以促进ER+乳腺癌的雌激素非依赖性生长。在雌激素缺乏的情况下，linc-RoR引起磷酸化MAPK/ERK通路的上调，这进而激活ER信号传导。linc-RoR的敲除消除了雌激素剥夺诱导的ERK激活以及ER磷酸化，而linc-RoR的重新表达恢复了所有上述表型。此外，我们发现ERK特异性磷酸酶双特异性磷酸酶7（DUSP 7），也称为MKP-X，参与linc-RoR KO诱导的MAPK/ERK信号转导抑制。有趣的是，linc-RoR KO增加了DUSP 7的蛋白质稳定性，导致ERK磷酸化的抑制。临床数据分析显示，DUSP 7在ER+乳腺癌样品中的表达低于ER-乳腺癌样品。此外，DUSP 7表达的下调与患者存活率差相关。综上所述，这些结果表明linc-RoR通过调节ERK特异性磷酸酶DUSP 7促进乳腺癌细胞的雌激素非依赖性生长和MAPK/ERK通路的激活。因此，本研究不仅有助于建立linc-RoR在ER+乳腺癌的雌激素非依赖性和他莫昔芬耐药中的作用，而且还表明linc-RoR与MAPK/ERK通路之间的联系。本文的在线版本（10.1186/s12943-017-0727-3）包含补充材料，可供授权用户使用。
The conversion from estrogen-dependent to estrogen-independent state of ER+ breast cancer cells is the key step to promote resistance to endocrine therapies. Although the crucial role of MAPK/ERK signaling pathway in estrogen-independent breast cancer cell growth is well established, the underlying mechanism is not fully understood. In this study, we profiled lncRNA expression against a focused group of lncRNAs selected from lncRNA database. CRISPR/Cas9 was employed to knockout (KO) linc-RoR in MCF-7 cells, while rescue experiments were carried out to re-express linc-RoR in KO cells. Colony formation and MTT assays were used to examine the role of linc-RoR in estrogen-independent growth and tamoxifen resistance. Western blot and qRT-PCR were used to determine the change of protein and lncRNA levels, respectively. The expression of DUSP7 in clinical specimens was downloaded from Oncomine (www.oncomine.org) and the dataset from Kaplan-Meier Plotter (http://kmplot.com) was used to analyze the clinical outcomes in relation to DUSP7. We identified that linc-RoR functions as an onco-lncRNA to promote estrogen-independent growth of ER+ breast cancer. Under estrogen deprivation, linc-RoR causes the upregulation of phosphorylated MAPK/ERK pathway which in turn activates ER signaling. Knockout of linc-RoR abrogates estrogen deprivation-induced ERK activation as well as ER phosphorylation, whereas re-expression of linc-RoR restores all above phenotypes. Moreover, we show that the ERK-specific phosphatase Dual Specificity Phosphatase 7 (DUSP7), also known as MKP-X, is involved in linc-RoR KO-induced repression of MAPK/ERK signaling. Interestingly, linc-RoR KO increases the protein stability of DUSP7, resulting in repression of ERK phosphorylation. Clinical data analysis reveal that DUSP7 expression is lower in ER+ breast cancer samples than that in ER- breast cancer. Moreover, downregulation of DUSP7 expression is associated with poor patient survival. Taken together, these results suggest that linc-RoR promotes estrogen-independent growth and activation of MAPK/ERK pathway of breast cancer cells by regulating the ERK-specific phosphatase DUSP7. Thus, this study might help not only in establishing a role for linc-RoR in estrogen-independent and tamoxifen resistance of ER+ breast cancer, but also suggesting a link between linc-RoR and MAPK/ERK pathway. The online version of this article (10.1186/s12943-017-0727-3) contains supplementary material, which is available to authorized users.
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