Induction of cell proliferation and survival genes by estradiol-repressed microRNAs in breast cancer cells.
Induction of cell proliferation and survival genes by estradiol-repressed microRNAs in breast cancer cells.
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乳腺癌细胞中雌二醇抑制的 microRNA 诱导细胞增殖和存活基因。
DOI：
10.1186/1471-2407-12-29
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发表时间：
2012-01-20
期刊：
影响因子：
3.8
通讯作者：
Luo D
中科院分区：
文献类型：
--
作者：
Yu X;Zhang X;Dhakal IB;Beggs M;Kadlubar S;Luo D
在雌激素应答的MCF-7细胞中，雌二醇（E2）与ERα结合导致参与细胞增殖和存活控制的基因的转录调控。MicroRNAs （miRNAs）已成为基因表达的关键转录后调控因子。本研究的目的是探讨mirna是否参与激素调节雌激素应答基因的表达。Western blot和QPCR分别检测雌激素应答基因和mirna的表达。通过荧光素酶报告基因检测和转染miRNA模拟物或抑制剂来验证miRNA调控的靶基因表达。MTS法观察细胞增殖情况。E2通过抑制MCF-7细胞中一组mirna （miR-16、miR-143、miR-203）的水平显著诱导bcl-2、cyclin D1和survivin的表达。MiRNA转染和荧光素酶检测证实bcl-2受miR-16和miR-143调控，cyclinD1受miR-16调控。重要的是，survivin被miR-16、miR-143、miR-203靶向。E2的调节作用可被抗雌激素的ICI 182、780和雷洛昔芬预处理取消，或被ERα siRNA破坏，表明E2的调节依赖于ERα。为了研究这些miRNAs在雌激素应答细胞中的功能意义，我们将miRNAs模拟物转染到MCF-7细胞中。结果表明，过表达这些miRNAs可显著抑制e2诱导的细胞增殖。对mirna表达的进一步研究表明，miR-16、miR-143和miR-203在三阳性乳腺癌组织中高表达，提示这些mirna在ER阳性乳腺癌中具有潜在的抑瘤作用。这些结果表明，E2通过协调一组mirna的下调来诱导bcl-2、cyclin D1和survivin。反过来，这些mirna表现出生长抑制作用，并在E2的作用下控制细胞增殖。这为mirna对细胞增殖和存活基因的整体转录后调控提供了新的见解，这是乳腺癌的潜在治疗选择。
In estrogen responsive MCF-7 cells, estradiol (E2) binding to ERα leads to transcriptional regulation of genes involved in the control of cell proliferation and survival. MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression. The aim of this study was to explore whether miRNAs were involved in hormonally regulated expression of estrogen responsive genes. Western blot and QPCR were used to determine the expression of estrogen responsive genes and miRNAs respectively. Target gene expression regulated by miRNAs was validated by luciferase reporter assays and transfection of miRNA mimics or inhibitors. Cell proliferation was evaluated by MTS assay. E2 significantly induced bcl-2, cyclin D1 and survivin expression by suppressing the levels of a panel of miRNAs (miR-16, miR-143, miR-203) in MCF-7 cells. MiRNA transfection and luciferase assay confirmed that bcl-2 was regulated by miR-16 and miR-143, cyclinD1 was modulated by miR-16. Importantly, survivin was found to be targeted by miR-16, miR-143, miR-203. The regulatory effect of E2 can be either abrogated by anti-estrogen ICI 182, 780 and raloxifene pretreatment, or impaired by ERα siRNA, indicating the regulation is dependent on ERα. In order to investigate the functional significance of these miRNAs in estrogen responsive cells, miRNAs mimics were transfected into MCF-7 cells. It revealed that overexpression of these miRNAs significantly inhibited E2-induced cell proliferation. Further study of the expression of the miRNAs indicated that miR-16, miR-143 and miR-203 were highly expressed in triple positive breast cancer tissues, suggesting a potential tumor suppressing effect of these miRNAs in ER positive breast cancer. These results demonstrate that E2 induces bcl-2, cyclin D1 and survivin by orchestrating the coordinate downregulation of a panel of miRNAs. In turn, the miRNAs manifest growth suppressive effects and control cell proliferation in response to E2. This sheds a new insight into the integral post-transcriptional regulation of cell proliferation and survival genes by miRNAs, a potential therapeutic option for breast cancer.
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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
影响因子：
5.4
作者：
Borralho, Pedro M.;Kren, Betsy T.;Rodrigues, Cecilia M. P.
通讯作者：
Rodrigues, Cecilia M. P.
影响因子：
30.8
作者：
Carroll, Jason S.;Meyer, Clifford A.;Brown, Myles
通讯作者：
Brown, Myles
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：
82.9
作者：
Bonci, Desiree;Coppola, Valeria;De Maria, Ruggero
通讯作者：
De Maria, Ruggero