CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKKα.
CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKKα.
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引用2通过对IKKα的影响调节乳腺癌转移性能力。
DOI：
10.1158/1541-7786.mcr-16-0081
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
Kominsky SL
中科院分区：
文献类型：
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作者：
Jayaraman S;Doucet M;Lau WM;Kominsky SL
先前，我们使用小鼠乳腺癌模型鉴定了转录共激活因子CITED 2作为骨转移的潜在促进剂。将这些研究扩展到人乳腺癌，观察到相对于原发性肿瘤，转移性乳腺癌的患者样本中CITED 2 mRNA表达显著升高，相对于非骨部位，骨转移的水平最高。为了进一步评估CITED 2在乳腺癌转移中的功能，CITED 2表达在人乳腺癌细胞系MDA-MB-231和MDA-MB-468中稳定降低，所述细胞系在动物模型中是转移性的。虽然CITED 2敲除对细胞增殖没有影响，但细胞迁移和侵袭显着减少，无胸腺裸小鼠心脏内给药后转移的建立也显着减少。为了探索这些作用背后的机制，通过cDNA微阵列进行了MDA-MB-231细胞中CITED 2敲低后的基因表达。正如在MDA-MB-231和MDA-MB-468细胞中的mRNA和蛋白水平所证实的，NF-κB调节剂IKKα的表达显著降低沿着几种已知在转移中起作用的NF-κB靶点（OPN、MMP 9、uPA、TNF α、IL-11和IL-1β）的表达也显著降低。此外，ChIP检测显示CITED 2募集到IKKα的启动子，表明在调节其表达中起直接作用。与IKKα表达降低一致，CITED 2敲低抑制经典和非经典NF-κB信号传导。最后，在MDA-MB-231和MDA-MB-468细胞中，CITED 2敲低后IKKα表达的恢复挽救了它们的侵袭能力。总的来说，这些数据表明CITED 2调节人乳腺癌细胞的转移能力，至少部分是通过调节IKKα。目前的研究强调了CITED 2在促进乳腺癌转移中的作用，部分通过调节IKKα。
Previously, we identified the transcriptional co-activator CITED2 as a potential facilitator of bone metastasis using a murine mammary cancer model. Extending these studies to human breast cancer, it was observed that CITED2 mRNA expression was significantly elevated in patient specimens of metastatic breast cancer relative to primary tumors, with highest levels in metastasis to bone relative to non-bone sites. To further evaluate CITED2 functions in breast cancer metastasis, CITED2 expression was stably reduced in the human breast cancer cell lines MDA-MB-231 and MDA-MB-468, which are metastatic in animal models. While CITED2 knockdown had no effect on cell proliferation, cell migration and invasion were significantly reduced, as was the establishment of metastasis following intra-cardiac administration in athymic nude mice. To explore the mechanism behind these effects, gene expression following CITED2 knockdown in MDA-MB-231 cells by cDNA microarray was performed. As confirmed at the mRNA and protein levels in both MDA-MB-231 and MDA-MB-468 cells, expression of the NF-κB regulator IKKα was significantly reduced along with several NF-κB targets with known roles in metastasis (OPN, MMP9, uPA, SPARC, IL-11 and IL-1β). Further, ChIP assay revealed recruitment of CITED2 to the promoter of IKKα, indicating a direct role in regulating its expression. Consistent with reduced IKKα expression, CITED2 knockdown inhibited both canonical and non-canonical NF-κB signaling. Finally, restoration of IKKα expression following CITED2 knockdown in MDA-MB-231 and MDA-MB-468 cells rescued their invasive ability. Collectively, these data demonstrate that CITED2 modulates metastatic ability in human breast cancer cells, at least in part, through the regulation of IKKα. The current study highlights the role of CITED2 in facilitating breast cancer metastasis, partly via regulation of IKKα.