Crucial role for early growth response-1 in the transcriptional regulation of miR-20b in breast cancer.
Crucial role for early growth response-1 in the transcriptional regulation of miR-20b in breast cancer.
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早期生长反应1在miR-20b转录调节乳腺癌中的关键作用。
DOI：
10.18632/oncotarget.1165
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Kovalchuk O
中科院分区：
文献类型：
--
作者：
Li D;Ilnytskyy Y;Kovalchuk A;Khachigian LM;Bronson RT;Wang B;Kovalchuk O
控制乳腺癌发病机制的miRNAs的转录调控在很大程度上仍然未知。在这里，我们发现，电离辐射，一种已知的乳腺癌致癌物质，触发了乳腺组织中miR-20 b的差异表达。我们在miR-20 b启动子中鉴定了锌指转录因子早期生长反应-1（EGR 1）的几个富含GC的共有结合基序。miR-20 b在乳腺癌细胞系HCC 1806中被IR上调，并且其上调与EGR 1表达相关。因此，我们以HCC 1806细胞为模型系统，探讨EGFR 1在miR-20 b转录中的作用。siRNA敲除EGR 1减弱miR-20 b表达。荧光素酶测定显示，EGR 1刺激由野生型miR-20 b启动子驱动的荧光素酶活性，而这种诱导在突变型miR-20启动子构建体中被消除。我们注意到，与正常人乳腺上皮细胞相比，HCC 1806细胞中miR-20 b启动子处的EGFR 1显著富集。抑制miR-20 b可显著抑制HCC 1806细胞的增殖和迁移，并导致细胞阻滞于G 0/G1期和S期。体外RNA下拉分析表明，miR-20 b靶向许多肿瘤抑制因子，包括在HCC 1806中下调的PTEN和BRCA 1。相反，miR-20 b的抑制增加了PTEN和BRCA 1水平。此外，免疫组化和FISH分析显示，乳腺癌组织中miR-20 b的表达与EGFR 1水平显著相关。因此，我们的研究结果首次证明，EGFR 1是miR-20 b转录控制的关键参与者，而miR-20 b可能反过来作为癌基因通过肿瘤抑制因子靶向促进乳腺肿瘤发生。
Transcriptional regulation of miRNAs that control the pathogenesis of breast cancer remains largely unknown. Here, we showed that ionizing radiation, a known breast carcinogen, triggered the differential expression of miR-20b in mammary tissues. We identified several GC-rich consensus binding motifs for the zinc finger transcription factor early growth response-1 (EGR1) in miR-20b promoter. miR-20b was upregulated by IR and its upregulation correlated with EGR1 expression in the breast cancer cell line HCC1806. Therefore, we used HCC1806 cells as a model system to explore the role of EGR1 in miR-20b transcription. siRNA knockdown of EGR1 attenuated miR-20b expression. Luciferase assays showed that whereas EGR1 stimulated luciferase activity driven by the wild-type miR-20b promoter, this induction was abolished in the mutant miR-20 promoter construct. We noted significant enrichment of EGR1 at miR-20b promoter in HCC1806 cells compared with normal human mammary epithelial cells. Suppression of miR-20b significantly inhibited HCC1806 cell proliferation and migration, and led to G 0/G 1 and S phase arrest. In vitro RNA-pull down assays indicated that miR-20b targets numerous tumor suppressors, including PTEN and BRCA1, which were downregulated in HCC1806. Conversely, suppression of miR-20b increased PTEN and BRCA1 levels. Moreover, immunohistochemical and FISH analyses showed that the miR-20b expression correlated significantly with EGR1 levels in breast cancer tissues. Our findings thus demonstrate for the first time that EGR1 is a key player in the transcriptional control of miR-20b, and miR-20b may in turn function as an oncogene by contributing to breast tumorigenesis via tumor suppressor targeting.
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影响因子：
14.8
作者：
de Planell-Saguer, Mariangels;Celina Rodicio, Maria;Mourelatos, Zissimos
通讯作者：
Mourelatos, Zissimos
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：
37.8
作者：
Chen, WJ;Lin, KH;Pang, JHS
通讯作者：
Pang, JHS
影响因子：
20.3
作者：
Inomata, Mika;Tagawa, Hiroyuki;Sawada, Kenichi
通讯作者：
Sawada, Kenichi
影响因子：
4.3
作者：
Koturbash, Igor;Zemp, Franz J.;Kovalchuk, Olga
通讯作者：
Kovalchuk, Olga