Runx2 transcriptome of prostate cancer cells: insights into invasiveness and bone metastasis.
Runx2 transcriptome of prostate cancer cells: insights into invasiveness and bone metastasis.
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DOI：
10.1186/1476-4598-9-258
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发表时间：
2010-09-23
期刊：
影响因子：
37.3
通讯作者：
Frenkel B
中科院分区：
文献类型：
--
作者：
Baniwal SK;Khalid O;Gabet Y;Shah RR;Purcell DJ;Mav D;Kohn-Gabet AE;Shi Y;Coetzee GA;Frenkel B
前列腺癌（PCa）细胞至少部分地通过获得拟骨特性而优先转移到骨。Runx 2是一种成骨细胞主转录因子，在PCa细胞中异常表达，并促进其转移表型。Runx 2调控的转录程序在成骨细胞发生过程中得到了广泛的研究，其中它以上下文依赖的方式激活或抑制靶基因。然而，很少有人知道PCa细胞中Runx 2影响的基因调控网络。因此，我们研究了PCa细胞中响应Runx 2的全基因组mRNA表达变化。我们设计了一个C4-2B PCa亚系，称为C4-2B/Rx 2dox，其中多西环素（Dox）处理刺激Runx 2表达从非常低的水平在其他PCa细胞中观察到。使用全基因组表达阵列进行转录组分析，然后进行计算机分析，表明Runx 2上调了许多具有显著癌症相关功能的基因。它们包括分泌因子（CSF 2、SDF-1）、蛋白水解酶（MMP 9、CST 7）、细胞骨架调节剂（SDC 2、Twinfilin、SH 3 PXD 2A）、细胞内信号传导分子（DUSP 1、SPHK 1、RASD 1）和转录因子（Sox 9、SNAI 2、SMAD 3），这些因子在上皮向间充质转化（EMT）、组织侵袭以及归巢和附着于骨中起作用。与基因表达数据一致，C4-2B细胞中Runx 2的诱导增强了它们的侵袭性。它还通过阻断细胞周期进程中的G1/S期转变促进细胞静止。此外，细胞周期阻滞被逆转，因为Dox停药后Runx 2水平下降。Runx 2在C4-2B/Rx 2dox细胞中的作用，以及通过采用LNCaP、22 RV 1和PC 3细胞进行的类似观察，突出了Runx 2促进PCa细胞转移表型的多种机制，包括组织侵袭、归巢至骨和诱导高骨转换。因此，Runx 2是一个有吸引力的目标，用于开发新的诊断，预后和治疗方法，以PCa管理。靶向Runx 2可能比专注于其单个下游基因和途径更有效。
Prostate cancer (PCa) cells preferentially metastasize to bone at least in part by acquiring osteomimetic properties. Runx2, an osteoblast master transcription factor, is aberrantly expressed in PCa cells, and promotes their metastatic phenotype. The transcriptional programs regulated by Runx2 have been extensively studied during osteoblastogenesis, where it activates or represses target genes in a context-dependent manner. However, little is known about the gene regulatory networks influenced by Runx2 in PCa cells. We therefore investigated genome wide mRNA expression changes in PCa cells in response to Runx2. We engineered a C4-2B PCa sub-line called C4-2B/Rx2dox, in which Doxycycline (Dox) treatment stimulates Runx2 expression from very low to levels observed in other PCa cells. Transcriptome profiling using whole genome expression array followed by in silico analysis indicated that Runx2 upregulated a multitude of genes with prominent cancer associated functions. They included secreted factors (CSF2, SDF-1), proteolytic enzymes (MMP9, CST7), cytoskeleton modulators (SDC2, Twinfilin, SH3PXD2A), intracellular signaling molecules (DUSP1, SPHK1, RASD1) and transcription factors (Sox9, SNAI2, SMAD3) functioning in epithelium to mesenchyme transition (EMT), tissue invasion, as well as homing and attachment to bone. Consistent with the gene expression data, induction of Runx2 in C4-2B cells enhanced their invasiveness. It also promoted cellular quiescence by blocking the G1/S phase transition during cell cycle progression. Furthermore, the cell cycle block was reversed as Runx2 levels declined after Dox withdrawal. The effects of Runx2 in C4-2B/Rx2dox cells, as well as similar observations made by employing LNCaP, 22RV1 and PC3 cells, highlight multiple mechanisms by which Runx2 promotes the metastatic phenotype of PCa cells, including tissue invasion, homing to bone and induction of high bone turnover. Runx2 is therefore an attractive target for the development of novel diagnostic, prognostic and therapeutic approaches to PCa management. Targeting Runx2 may prove more effective than focusing on its individual downstream genes and pathways.
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DOI：
10.1073/pnas.88.18.8024
发表时间：
1991-09-01
影响因子：
11.1
作者：
DONALIES, M;CRAMER, M;STARZINSKIPOWITZ, A
通讯作者：
STARZINSKIPOWITZ, A
影响因子：
5.8
作者：
Endo, Toyoshi;Ohta, Kazuyasu;Kobayashi, Tetsuro
通讯作者：
Kobayashi, Tetsuro
影响因子：
5.3
作者：
Geoffroy, V;Kneissel, M;Matthias, P
通讯作者：
Matthias, P
影响因子：
3.9
作者：
CHIANG, L;CONTRERAS, L;WARD, PH
通讯作者：
WARD, PH
Osf2/Cbfa1：成骨细胞分化的转录激活因子
影响因子：
64.5
作者：
Ducy, P;Zhang, R;Karsenty, G
通讯作者：
Karsenty, G