Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes glioma cell invasion through induction of NF-κB-inducing kinase (NIK) and noncanonical NF-κB signaling.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes glioma cell invasion through induction of NF-κB-inducing kinase (NIK) and noncanonical NF-κB signaling.
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DOI：
10.1186/s12943-014-0273-1
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发表时间：
2015-01-27
期刊：
影响因子：
37.3
通讯作者：
Sitcheran R
中科院分区：
文献类型：
--
作者：
Cherry EM;Lee DW;Jung JU;Sitcheran R
高级别胶质瘤是最具侵袭性和治疗抗性的癌症之一。我们最近发现非经典NF-κB/RelB信号是胶质瘤侵袭性间质亚型肿瘤发生和侵袭的有力驱动因素。然而，在胶质瘤中诱导非经典NF-κB信号通路激活的相关信号及其相对于经典NF-κB通路的功能仍然不清楚。采用三维胶原侵袭实验研究了肿瘤坏死因子（TNF）样弱凋亡诱导剂（TWEAK）调节NF-κB信号传导和促进肿瘤进展的能力。通过shRNA介导的功能丧失研究，评价特异性NF-κB蛋白在调节胶质瘤细胞侵袭和基质金属蛋白酶9（MMP 9）表达中的作用。利用原位异种移植小鼠模型研究了NF-κ B诱导激酶（NIK）促进胶质瘤生长的能力。在显示非经典NF-κB信号升高的胶质瘤细胞中，RelB的缺失减弱了侵袭而不影响RelA表达或磷酸化，并且RelB在RelA缺失的情况下足以促进侵袭。细胞因子TWEAK通过诱导p100加工成p52以及RelB和p52的核积累而优先激活非经典NF-κB途径，而不激活经典NF-κB途径。此外，TWEAK，而不是TNFα，显着增加NIK mRNA水平。TWEAK还促进非经典NFκ B依赖性MMP 9表达和胶质瘤细胞侵袭。最后，NIK的表达足以增加体内胶质瘤的发生。我们的数据证实了NIK和非经典NF-κB在介导TWEAK诱导的MMP依赖性胶质瘤细胞侵袭中的关键作用。研究结果还表明，TWEAK诱导非经典NF-κB信号和NIK mRNA表达的信号特异性调节。总之，这些研究揭示了非经典NF-κB信号在调节胶质瘤侵袭性中的重要作用，并突出了靶向激活NIK在这种致命疾病中的治疗潜力。本文的在线版本（doi：10.1186/s12943-014-0273-1）包含补充材料，可供授权用户使用。
High-grade gliomas are one of the most invasive and therapy-resistant cancers. We have recently shown that noncanonical NF-κB/RelB signaling is a potent driver of tumorigenesis and invasion in the aggressive, mesenchymal subtype of glioma. However, the relevant signals that induce activation of noncanonical NF-κB signaling in glioma and its function relative to the canonical NF-κB pathway remain elusive. The ability of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) to regulate NF-κB signaling and promote tumor progression was investigated in both established and primary high-grade glioma tumor lines using a three-dimensional (3-D) collagen invasion assay. The roles of specific NF-κB proteins in regulating glioma cell invasion and expression of Matrix Metalloproteinase 9 (MMP9) in response to TWEAK were evaluated using shRNA-mediated loss-of-function studies. The ability of NF-κB-inducing kinase (NIK) to promote glioma growth in vivo was investigated using an orthotopic xenograft mouse model. In glioma cells that display elevated noncanonical NF-κB signaling, loss of RelB attenuates invasion without affecting RelA expression or phosphorylation and RelB is sufficient to promote invasion in the absence of RelA. The cytokine TWEAK preferentially activates the noncanonical NF-κB pathway through induction of p100 processing to p52 and nuclear accumulation of both RelB and p52 without activating the canonical NF-κB pathway. Moreover, TWEAK, but not TNFα, significantly increases NIK mRNA levels. TWEAK also promotes noncanonical NFκB-dependent MMP9 expression and glioma cell invasion. Finally, expression of NIK is sufficient to increase gliomagenesis in vivo. Our data establish a key role for NIK and noncanonical NF-κB in mediating TWEAK-induced, MMP-dependent glioma cell invasion. The findings also demonstrate that TWEAK induces noncanonical NF-κB signaling and signal-specific regulation of NIK mRNA expression. Together, these studies reveal the important role of noncanonical NF-κB signaling in regulating glioma invasiveness and highlight the therapeutic potential of targeting activation of NIK in this deadly disease. The online version of this article (doi:10.1186/s12943-014-0273-1) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
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