MicroRNA-34c Inversely Couples the Biological Functions of the Runt-related Transcription Factor RUNX2 and the Tumor Suppressor p53 in Osteosarcoma
MicroRNA-34c Inversely Couples the Biological Functions of the Runt-related Transcription Factor RUNX2 and the Tumor Suppressor p53 in Osteosarcoma
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DOI：
10.1074/jbc.m112.445890
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发表时间：
2013-07-19
影响因子：
4.8
通讯作者：
van Wijnen, Andre J.
中科院分区：
文献类型：
--
作者：
van der Deen, Margaretha;Taipaleenmaeki, Hanna;van Wijnen, Andre J.
骨肉瘤（OS）是一种原发性骨肿瘤，最常见于青春期。RUNX 2，刺激分化和抑制成骨细胞的增殖，是失调的OS。在这里，我们定义的病理作用的RUNX 2 OS的病因和机制，RUNX 2的表达被刺激。RUNX 2通常在人OS活检和细胞系中高度表达。小干扰RNA介导的RUNX 2耗竭抑制U2 OS OS细胞的生长。在不同的OS细胞系和成骨细胞中，RUNX 2水平与p53（易患OS）的丢失呈负相关。RUNX 2蛋白水平在用MDM 2抑制剂Nutlin-3稳定p53后降低。与间充质祖细胞相比，RUNX 2蛋白表达升高是转录后调节的，并与人OS细胞中几种经验证的RUNX 2靶向microRNA的表达减少直接相关。p53依赖性miR-34 c是OS中最显著下调的RUNX 2靶向microRNAs。miR-34 c的外源性补充显著降低RUNX 2蛋白水平，而3 '-UTR报告基因测定确立RUNX 2为OS细胞中miR-34 c的直接靶标。重要的是，Nutlin-3介导的p53稳定增加了miR-34 c的表达并减少了RUNX 2。因此，一种新的p53-miR-34 c-RUNX 2网络控制骨细胞的细胞生长，并在OS中受损。
Osteosarcoma (OS) is a primary bone tumor that is most prevalent during adolescence. RUNX2, which stimulates differentiation and suppresses proliferation of osteoblasts, is deregulated in OS. Here, we define pathological roles of RUNX2 in the etiology of OS and mechanisms by which RUNX2 expression is stimulated. RUNX2 is often highly expressed in human OS biopsies and cell lines. Small interference RNA-mediated depletion of RUNX2 inhibits growth of U2OS OS cells. RUNX2 levels are inversely linked to loss of p53 (which predisposes to OS) in distinct OS cell lines and osteoblasts. RUNX2 protein levels decrease upon stabilization of p53 with the MDM2 inhibitor Nutlin-3. Elevated RUNX2 protein expression is post-transcriptionally regulated and directly linked to diminished expression of several validated RUNX2 targeting microRNAs in human OS cells compared with mesenchymal progenitor cells. The p53-dependent miR-34c is the most significantly down-regulated RUNX2 targeting microRNAs in OS. Exogenous supplementation of miR-34c markedly decreases RUNX2 protein levels, whereas 3'-UTR reporter assays establish RUNX2 as a direct target of miR-34c in OS cells. Importantly, Nutlin-3-mediated stabilization of p53 increases expression of miR-34c and decreases RUNX2. Thus, a novel p53-miR-34c-RUNX2 network controls cell growth of osseous cells and is compromised in OS.