Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.
Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.
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DOI：
10.1371/journal.pone.0037361
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kallioniemi O
中科院分区：
文献类型：
--
作者：
Pollari S;Leivonen SK;Perälä M;Fey V;Käkönen SM;Kallioniemi O
骨转移的发生依赖于骨微环境中癌细胞与骨细胞的相互作用。转化生长因子β在破骨细胞性骨吸收过程中从骨中释放出来，诱导乳腺癌细胞产生溶骨因子，如白介素11(IL-11)。IL-11反过来通过刺激破骨细胞功能增加骨溶解，启动癌症生长和骨破坏的恶性循环。我们的目标是鉴定和功能表征介导骨转移过程的microRNAs，重点是调节转化生长因子β诱导IL-11的miRNAs。首先，我们分析了455个miRNAs在高度骨转移的MDA-MB-231(SA)变异体中的表达，与亲代的MDA-MB-231乳腺癌细胞系相比，发现16个miRNAs(3.5%)在两种细胞类型中的表达差异是后者的3倍。然后，我们应用基于细胞的过度表达筛选与前miRNA构建，从功能上识别调节转化生长因子-β诱导的IL-11产生的miRNA。这项分析明确指出miR-204、miR-211和miR-379是这样的关键调节因子。这些miRNAs通过与其3‘端非编码区结合而直接靶向IL11。MIR-379也抑制Smad2/3/4介导的转录活性。基因表达分析表明，这些miRNAs下调了几个与转化生长因子-β信号转导有关的基因的表达，其中包括前列腺素-过氧化物合成酶2(PTGS2)。此外，miR-379下调的基因与乳腺癌基本亚型中上调的一组基因之间存在显著的相关性。综上所述，功能证据和临床相关性暗示了miRNAs与乳腺癌骨转移过程中关键步骤之间的新的机制联系，具有潜在的临床意义。
Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-β induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5%) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-β-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3′ UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-β signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance.
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DOI：
10.1093/bioinformatics/btr149
发表时间：
2011-05-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Ellwanger DC;Büttner FA;Mewes HW;Stümpflen V
通讯作者：
Stümpflen V
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
3.7
作者：
Hanavadi, Satheesha;Martin, Tracey A.;Jiang, Wen G.
通讯作者：
Jiang, Wen G.
DOI：
10.1073/pnas.0914785107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Conte, Ivan;Carrella, Sabrina;Banfi, Sandro
通讯作者：
Banfi, Sandro
影响因子：
16
作者：
Lal A;Navarro F;Maher CA;Maliszewski LE;Yan N;O'Day E;Chowdhury D;Dykxhoorn DM;Tsai P;Hofmann O;Becker KG;Gorospe M;Hide W;Lieberman J
通讯作者：
Lieberman J