Estrogen mediated-activation of miR-191/425 cluster modulates tumorigenicity of breast cancer cells depending on estrogen receptor status.
Estrogen mediated-activation of miR-191/425 cluster modulates tumorigenicity of breast cancer cells depending on estrogen receptor status.
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DOI：
10.1371/journal.pgen.1003311
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Croce CM
中科院分区：
文献类型：
--
作者：
Di Leva G;Piovan C;Gasparini P;Ngankeu A;Taccioli C;Briskin D;Cheung DG;Bolon B;Anderlucci L;Alder H;Nuovo G;Li M;Iorio MV;Galasso M;Santhanam R;Marcucci G;Perrotti D;Powell KA;Bratasz A;Garofalo M;Nephew KP;Croce CM
MicroRNA（miRNAs），单链非编码RNA，影响无数可能导致癌症的生物过程。尽管一些miRNAs具有肿瘤抑制和致癌功能，但大多数microRNAs促进和调节肿瘤发生的能力尚未得到研究。在这里，我们确定了miR-191/425簇在转录上依赖于宿主基因DALRD 3，并且激素17β-雌二醇（雌激素或E2）控制miR-191/425和DALRD 3的表达。miR-191/425基因座特征显示，雌激素受体α（ERα）募集到miR-191/425-DALRD 3单元的调控区导致miR-191和miR-425的积累，随后DALRD 3表达水平降低。我们证明了miR-191通过抑制肿瘤抑制因子EGR 1保护ERα阳性乳腺癌细胞免受激素饥饿诱导的凋亡。此外，侵袭性乳腺癌细胞中miR-191/425簇的强制表达改变了整体基因表达谱，使我们能够鉴定重要的肿瘤促进基因，包括SATB 1，CCND 2和FSCN 1，作为miR-191和miR-425的靶点。最后，体外和体内实验表明，miR-191和miR-425减少增殖，损害肿瘤发生和转移，并增加上皮标记物在侵袭性乳腺癌细胞中的表达。我们的数据为miR-191/425簇的转录调控及其在乳腺癌中的背景特异性生物决定因素提供了令人信服的证据。重要的是，我们证明了miR-191/425簇通过减少广泛的基因网络的表达，对乳腺癌细胞的癌症发生和进展具有根本性的影响。MicroRNA是一种小的非编码RNA，作为基因表达的转录后抑制因子。已经描述了miRNA在驱动各种恶性肿瘤（包括乳腺癌）的起始和进展的所有分子过程中的关键作用。已经证实正常和肿瘤性乳腺组织之间的差异性miRNA表达，以及乳腺癌分子亚型之间的差异性miRNA表达。超过一半的乳腺癌过度表达ERα，一些研究表明miRNA表达受ERα控制。我们评估了乳腺癌细胞中雌激素饥饿和刺激后microRNA表达的总体变化，并确定miR-191/425和宿主基因DALRD 3与ERα阳性肿瘤呈正相关。我们证明了ERα调节miR-191/425簇，并验证了一个转录网络的存在，该网络允许雌激素对miR-191/425及其宿主基因的双重作用。我们发现，雌激素诱导miR-191/425在体外和体内支持ERα阳性乳腺癌细胞的雌激素依赖性增殖。相反，miR-191/425簇重编程基因表达以损害高度侵袭性ERα阴性乳腺癌细胞的致瘤性和转移潜力。
MicroRNAs (miRNAs), single-stranded non-coding RNAs, influence myriad biological processes that can contribute to cancer. Although tumor-suppressive and oncogenic functions have been characterized for some miRNAs, the majority of microRNAs have not been investigated for their ability to promote and modulate tumorigenesis. Here, we established that the miR-191/425 cluster is transcriptionally dependent on the host gene, DALRD3, and that the hormone 17β-estradiol (estrogen or E2) controls expression of both miR-191/425 and DALRD3. MiR-191/425 locus characterization revealed that the recruitment of estrogen receptor α (ERα) to the regulatory region of the miR-191/425-DALRD3 unit resulted in the accumulation of miR-191 and miR-425 and subsequent decrease in DALRD3 expression levels. We demonstrated that miR-191 protects ERα positive breast cancer cells from hormone starvation-induced apoptosis through the suppression of tumor-suppressor EGR1. Furthermore, enforced expression of the miR-191/425 cluster in aggressive breast cancer cells altered global gene expression profiles and enabled us to identify important tumor promoting genes, including SATB1, CCND2, and FSCN1, as targets of miR-191 and miR-425. Finally, in vitro and in vivo experiments demonstrated that miR-191 and miR-425 reduced proliferation, impaired tumorigenesis and metastasis, and increased expression of epithelial markers in aggressive breast cancer cells. Our data provide compelling evidence for the transcriptional regulation of the miR-191/425 cluster and for its context-specific biological determinants in breast cancers. Importantly, we demonstrated that the miR-191/425 cluster, by reducing the expression of an extensive network of genes, has a fundamental impact on cancer initiation and progression of breast cancer cells. MicroRNAs are small noncoding RNAs that act as posttranscriptional repressors of gene expression. A pivotal role for miRNAs in all the molecular processes driving initiation and progression of various malignancies, including breast cancer, has been described. Divergent miRNA expression between normal and neoplastic breast tissues has been demonstrated, as well as differential miRNA expression among the molecular subtypes of breast cancer. Over half of all breast cancers overexpress ERα, and several studies have shown that miRNA expression is controlled by ERα. We assessed the global change in microRNA expression after estrogen starvation and stimulation in breast cancer cells and identified that miR-191/425 and the host gene DALRD3 are positively associated to ERα-positive tumors. We demonstrated that ERα regulates the miR-191/425 cluster and verified the existence of a transcriptional network that allows a dual effect of estrogen on miR-191/425 and their host gene. We show that estrogen induction of miR-191/425 supports in vitro and in vivo the estrogen-dependent proliferation of ERα positive breast cancer cells. On the contrary, miR-191/425 cluster reprograms gene expression to impair tumorigenicity and metastatic potential of highly aggressive ERα negative breast cancer cells.
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影响因子：
11.2
作者：
Elyakim, Eran;Sitbon, Einat;Yerushalmi, Noga
通讯作者：
Yerushalmi, Noga
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：
3.3
作者：
Abdulkadir, SA;Carbone, JM;Milbrandt, J
通讯作者：
Milbrandt, J
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：
10.3
作者：
JIANG, SY;JORDAN, VC
通讯作者：
JORDAN, VC