Neurotensin signaling regulates stem-like traits of glioblastoma stem cells through activation of IL-8/CXCR1/STAT3 pathway.
Neurotensin signaling regulates stem-like traits of glioblastoma stem cells through activation of IL-8/CXCR1/STAT3 pathway.
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神经降压素信号通过激活 IL-8/CXCR1/STAT3 通路调节胶质母细胞瘤干细胞的干细胞样特征。
DOI：
10.1016/j.cellsig.2014.08.027
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发表时间：
2014-12
影响因子：
4.8
通讯作者：
Minhui Xu
中科院分区：
文献类型：
--
作者：
Ouyang Qing;Lunshan Xu;Hongjuan Cui;Minhui Xu
我们最近发现神经降压素（NTS）及其主要受体NTSR 1在胶质母细胞瘤细胞增殖和侵袭中起着至关重要的作用。然而，关于NTS/NTSR 1信号在胶质母细胞瘤干细胞（GSC）中的功能作用知之甚少。在这里，我们发现NTSR 1在GSC中比其非GSC对应物高表达。使用SR 48692或慢病毒介导的NTSR 1敲低进行药理学阻断可有效降低从胶质母细胞瘤细胞系和胶质母细胞瘤组织分离的GSC中的球体形成能力和干细胞标志物（如巢蛋白和Sox 2）的表达。相反，用NTS处理的GSC导致肿瘤球形成增加。从机制上讲，我们证明了EGFR依赖性的IL-8分泌增强是NTS信号在调节干细胞样性状中的作用的原因。最后，我们发现NTSR 1或IL-8敲低降低了转录因子STAT 3在Tyr 705的磷酸化，这是一个主要的转录因子参与GSC干细胞样性状的调节。虽然CXCR 1和CXCR 2抑制都减少了肿瘤球的形成，但我们发现CXCR 1而不是CXCR 2主要负责STAT 3磷酸化。综上所述，我们的研究结果表明，NTS/IL-8/CXCR 1/STAT 3信号传导对于维持GSC中的干细胞样特征至关重要，并为胶质母细胞瘤治疗提供了潜在的治疗靶点。
We recently found that neurotensin (NTS) and its primary receptor NTSR1 play a crucial role in glioblastoma cell proliferation and invasion. However, very little is known regarding the functional role of NTS/NTSR1 signaling in glioblastoma stem cells (GSCs). Here, we showed that NTSR1 is highly expressed in GSCs than its non-GSC counterparts. Pharmacological blockade with SR48692 or lentivirus mediated knockdown of NTSR1 efficiently reduced the sphere-forming ability and expression of stem cell markers such as nestin and Sox2 in GSCs isolated from glioblastoma cell line and glioblastoma tissues. Conversely, treated GSCs with NTS led to increase of tumor sphere formation. Mechanistically, we demonstrated that EGFR-dependent enhancement of IL-8 secretion is responsible for the effect of NTS signaling in the regulation of stem-like traits. Finally, we showed that NTSR1 or IL-8 knockdown decreased the phosphorylation of transcriptional factor STAT3 at Tyr705, which is a major transcription factor implicated in the regulation of GSC stem-like traits. Although both CXCR1 and CXCR2 inhibition reduced the tumor sphere formation, we found that CXCR1, but not CXCR2, is primarily responsible for STAT3 phosphorylation. Taken together, our findings suggest that NTS/IL-8/CXCR1/STAT3 signaling is crucial for the maintenance of stem-like traits in GSCs and provides a potential therapeutic target for glioblastoma therapy.
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影响因子：
8
作者：
Bonavia, R.;Inda, M. M.;Vandenberg, S.;Cheng, S-Y;Nagane, M.;Hadwiger, P.;Tan, P.;Sah, D. W. Y.;Cavenee, W. K.;Furnari, F. B.
通讯作者：
Furnari, F. B.
影响因子：
23.9
作者：
Pietras, Alexander;Katz, Amanda M.;Ekstroem, Elin J.;Wee, Boyoung;Halliday, John J.;Pitter, Kenneth L.;Werbeck, Jillian L.;Amankulor, Nduka M.;Huse, Jason T.;Holland, Eric C.
通讯作者：
Holland, Eric C.
影响因子：
3.9
作者：
Raychaudhuri, Baisakhi;Vogelbaum, Michael A.
通讯作者：
Vogelbaum, Michael A.
影响因子：
4.7
作者：
Kortleven, Christian;Bruneau, Laura Charlotte;Trudeau, Louis-Eric
通讯作者：
Trudeau, Louis-Eric
DOI：
10.1074/jbc.m104942200
发表时间：
2001-11
期刊：
The Journal of Biological Chemistry
影响因子：
--
作者：
Dezheng Zhao;A. C. Keates;Sabina Kuhnt-Moore;M. Moyer;C. Kelly;C. Pothoulakis
通讯作者：
Dezheng Zhao;A. C. Keates;Sabina Kuhnt-Moore;M. Moyer;C. Kelly;C. Pothoulakis