An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response in MCF-7 breast cancer cells.
An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response in MCF-7 breast cancer cells.
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DOI：
10.1261/rna.056895.116
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Sethupathy P
中科院分区：
文献类型：
--
作者：
Baran-Gale J;Purvis JE;Sethupathy P
雌激素受体α（ERα）是反映乳腺癌严重程度的重要生物标志物，也是乳腺癌治疗的常用靶点。在雌激素的作用下，ERα刺激包括编码和非编码RNA在内的动态转录程序。我们通过对MCF-7细胞（乳腺癌的ER+模型细胞系）中的信使RNA（mRNA）和microRNA（miRNA）进行时间分析来生成表达动态的精细比例图。我们确定了三个主要的表达趋势-瞬时的，诱导的，和抑制的，每一个丰富的基因具有不同的细胞功能。mRNA和miRNA时间表达谱的综合分析确定miR-503是雌激素反应的最强候选主调节因子，部分通过抑制ZNF 217-一种在癌症中经常扩增的癌基因。我们通过实验证实了miR-503直接靶向ZNF 217，并且miR-503的过表达抑制MCF-7细胞增殖。此外，ZNF 217和miR-503的水平与乳腺癌患者队列中相反的结果相关，ZNF 217的高表达与较差的生存率相关，而miR-503的高表达与改善的生存率相关。总体而言，这些数据表明miR-503作为一种有效的雌激素诱导的候选肿瘤抑制miRNA，可以抑制细胞增殖，并有望成为乳腺癌的新型治疗药物。更一般地说，我们的工作提供了一个系统级的框架，确定功能的相互作用，形状的基因表达的时间动态。
Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. In response to estrogen, ERα stimulates a dynamic transcriptional program including both coding and noncoding RNAs. We generate a fine-scale map of expression dynamics by performing a temporal profiling of both messenger RNAs (mRNAs) and microRNAs (miRNAs) in MCF-7 cells (an ER+ model cell line for breast cancer) in response to estrogen stimulation. We identified three primary expression trends—transient, induced, and repressed—that were each enriched for genes with distinct cellular functions. Integrative analysis of mRNA and miRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217—an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that overexpression of miR-503 suppresses MCF-7 cell proliferation. Moreover, the levels of ZNF217 and miR-503 are associated with opposite outcomes in breast cancer patient cohorts, with high expression of ZNF217 associated with poor survival and high expression of miR-503 associated with improved survival. Overall, these data indicate that miR-503 acts as a potent estrogen-induced candidate tumor suppressor miRNA that opposes cellular proliferation and has promise as a novel therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression.
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影响因子：
3
作者：
Clark NR;Hu KS;Feldmann AS;Kou Y;Chen EY;Duan Q;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
14.9
作者：
Bhat-Nakshatri P;Wang G;Collins NR;Thomson MJ;Geistlinger TR;Carroll JS;Brown M;Hammond S;Srour EF;Liu Y;Nakshatri H
通讯作者：
Nakshatri H
DOI：
10.1073/pnas.0906947106
发表时间：
2009-09-15
影响因子：
11.1
作者：
Castellano, Leandro;Giamas, Georgios;Stebbing, Justin
通讯作者：
Stebbing, Justin
影响因子：
3.7
作者：
Baran-Gale J;Fannin EE;Kurtz CL;Sethupathy P
通讯作者：
Sethupathy P
影响因子：
1.9
作者：
Higa GM;Fell RG
通讯作者：
Fell RG