Essential role of cooperative NF-κB and Stat3 recruitment to ICAM-1 intronic consensus elements in the regulation of radiation-induced invasion and migration in glioma.
Essential role of cooperative NF-κB and Stat3 recruitment to ICAM-1 intronic consensus elements in the regulation of radiation-induced invasion and migration in glioma.
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DOI：
10.1038/onc.2012.546
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发表时间：
2013-10-24
期刊：
影响因子：
8
通讯作者：
Rao, J. S.
中科院分区：
文献类型：
--
作者：
Kesanakurti, D.;Chetty, C.;Maddirela, D. Rajasekhar;Gujrati, M.;Rao, J. S.
关键词：
虽然放射治疗提高了患者的存活率，但即使在放射治疗(IR)后，随着肿瘤转移和侵袭的增加，基底节瘤往往会复发。在一些人类肿瘤中发现了异常的NF-κB和STAT3的激活和相互作用。然而，可能的NF-κB/STAT3相互作用以及STAT3在维持胶质母细胞瘤中的NF-κB核滞留中的作用仍不清楚。在神经胶质瘤中，STAT3和NF-κB(P65)在核内相互作用。最重要的是，GST下拉试验证实STAT3与p65反式激活结构域(TAD)结合，并存在于NF-κBDNA结合复合体中。在人胶质瘤异种移植细胞系4910和5310中，辐射显著增加了核磷酸化p65/磷酸化STAT3相互作用，并与ICAM-1和sICAM-1水平升高、迁移和侵袭相关。ChIP和启动子荧光素酶活性分析证实，在IR诱导的细胞间黏附分子-1表达中，邻近的内含子-1上的NF-κB(+399)和STAT3(+479)结合基序在上调表达中起着关键作用。用STAT3、siRNA或JSH-23特异性抑制STAT3和NF-κB可显著抑制IR诱导的p65在ICAM-1内含子-1上的募集，并抑制两种细胞的迁移特性。另一方面，在p65基因敲除细胞中，Stat3C或IR诱导的STAT3启动子募集显著减少，从而暗示了p65和STAT3之间的相互调节。我们还观察到，在Stat3C过表达的细胞中，NF-κB对ICAM-1内含子-1和ICAM-1反式激活的富集率显著增加。在体内原位实验中，Stat3.si+IR处理的小鼠肿瘤生长的抑制与IR诱导的p-p65/p-STAT3核共定位和ICAM-1水平的抑制有关。据我们所知，这是第一个显示核转录因子κB/STAT3在IR诱导的细胞间黏附分子-1调控中的关键作用的研究，并暗示靶向NF-κB/STAT3相互作用在胶质瘤治疗中可能具有未来的治疗意义。
Although radiotherapy improves survival in patients, GBMs tend to relapse with augmented tumor migration and invasion even after irradiation (IR). Aberrant NF-κB and Stat3 activation and interaction has been suggested in several human tumors. However, possible NF-κB/Stat3 interaction and the role of Stat3 in maintenance of NF-κB nuclear retention in glioblastoma (GBM) still remain unknown. Stat3 and NF-κB (p65) physically interact with one another in the nucleus in glioma tumors. Most importantly, GST pull-down assays identified that Stat3 binds to the p65 transactivation domain (TAD) and is present in the NF-κB DNA-binding complex. Irradiation significantly elevated nuclear phospho-p65/phospho-Stat3 interaction in correlation with increased ICAM-1 and sICAM-1 levels, migration and invasion in human glioma xenograft cell lines 4910 and 5310. ChIP and promoter luciferase activity assays confirmed the critical role of adjacent NF-κB (+399) and Stat3 (+479) binding motifs in the proximal intron-1 in elevating IR-induced ICAM-1 expression. Specific inhibition of Stat3 and NF-κB with Stat3.siRNA or JSH-23 severely inhibited IR-induced p65 recruitment onto ICAM-1 intron-1 and suppressed migratory properties in both cell lines. On the other hand, Stat3C- or IR-induced Stat3 promoter recruitment was significantly decreased in p65-knockdown cells, thereby suggesting the reciprocal regulation between p65 and Stat3. We also observed a significant increase in NF-κB enrichment on ICAM-1 intron-1 and ICAM-1 transactivation in Stat3C overexpressing cells. In in vivo orthotopic experiments, suppression of tumor growth in Stat3.si+IR-treated mice was associated with the inhibition of IR-induced p-p65/p-Stat3 nuclear-colocalization and ICAM-1 levels. To our knowledge, this is the first study showing the crucial role of NF-κB/Stat3 nuclear association in IR-induced ICAM-1 regulation and implies that targeting NF-κB/Stat3 interaction may have future therapeutic significance in glioma treatment.
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影响因子：
50.3
作者：
Lee H;Herrmann A;Deng JH;Kujawski M;Niu G;Li Z;Forman S;Jove R;Pardoll DM;Yu H
通讯作者：
Yu H
影响因子：
3.7
作者：
Kesanakurti D;Chetty C;Bhoopathi P;Lakka SS;Gorantla B;Tsung AJ;Rao JS
通讯作者：
Rao JS
影响因子：
11.2
作者：
Lee H;Deng J;Xin H;Liu Y;Pardoll D;Yu H
通讯作者：
Yu H
DOI：
10.1038/sj.neo.7900034
发表时间：
1999-08-01
期刊：
Neoplasia (New York)
影响因子：
--
作者：
Berens, Michael E.;Giese, Alf
通讯作者：
Giese, Alf
影响因子：
20.3
作者：
Lam, Lloyd T.;Wright, George;Staudt, Louis M.
通讯作者：
Staudt, Louis M.