TRPM7 channels regulate glioma stem cell through STAT3 and Notch signaling pathways.
TRPM7 channels regulate glioma stem cell through STAT3 and Notch signaling pathways.
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DOI：
10.1016/j.cellsig.2014.08.020
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发表时间：
2014-12
影响因子：
4.8
通讯作者：
Xiong ZG
中科院分区：
文献类型：
--
作者：
Liu M;Inoue K;Leng T;Guo S;Xiong ZG
多形性胶质母细胞瘤（GBM）是成人中最常见和最具侵袭性的原发性脑肿瘤，中位生存时间为14.6个月。一小部分癌症干细胞（CSC）启动并维持肿瘤，从而驱动胶质瘤肿瘤发生并负责对经典化疗和放疗的抗性。希望鉴定与CSC相关的信号通路以开发选择性靶向它们的新疗法。瞬时受体电位阳离子通道，亚家族M，成员7，也称为TRPM 7，是一种普遍存在的、Ca 2+和Mg 2+可渗透的离子通道，其特殊之处在于既是离子通道又是丝氨酸/苏氨酸激酶。在对TRPM 7沉默的胶质瘤细胞的研究中，我们证明了Notch（Notch 1、JAG 1、Hey 2和Survivin）和STAT 3通路在单层生长的胶质瘤细胞中下调。此外，与单层培养物相比，球状体胶质瘤CSC中磷酸化STAT 3、Notch靶基因和CSC标志物（ALDH 1和CD 133）显著更高。结果进一步显示酪氨酸磷酸化的STAT 3结合并激活胶质瘤细胞中的ALDH 1启动子。我们发现TRMP 7诱导的ALDH 1表达上调与ALDH 1活性增加相关，并且当作为球状体CSC扩增时，在干细胞样细胞中可检测到。最后，TRPM 7促进胶质瘤细胞的增殖、迁移和侵袭。这些证明TRPM 7激活JAK 2/STAT 3和/或Notch信号通路，并导致细胞增殖和迁移增加。这些发现首次证明TRPM 7（1）激活以前未被识别的STAT 3 → ALDH 1通路，（2）促进胶质瘤细胞中ALDH 1活性的诱导。
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults with median survival time of 14.6 months. A small fraction of cancer stem cells (CSC) initiate and maintain tumors thus driving glioma tumorigenesis and being responsible for resistance to classical chemo- and radio-therapies. It is desirable to identify signaling pathways related to CSC to develop novel therapies to selectively target them. Transient receptor potential cation channel, subfamily M, member 7, also known as TRPM7 is a ubiquitous, Ca2+ and Mg2+ permeable ion channels that are special in being both an ion channel and a serine/threonine kinase. In studies of glioma cells silenced for TRPM7, we demonstrated that Notch (Notch1, JAG1, Hey2, and Survivin) and STAT3 pathways are down regulated in glioma cells grown in monolayer. Furthermore, phospho-STAT3, Notch target genes and CSC markers (ALDH1 and CD133) were significantly higher in spheroid glioma CSCs when compared with monolayer cultures. The results further show that tyrosine-phosphorylated STAT3 binds and activates the ALDH1 promoters in glioma cells. We found that TRMP7-induced upregulation of ALDH1 expression is associated with increases in ALDH1 activity and is detectable in stem-like cells when expanded as spheroid CSCs. Finally, TRPM7 promotes proliferation, migration and invasion of glioma cells. These demonstrate that TRPM7 activates JAK2/STAT3 and/or Notch signaling pathways and leads to increased cell proliferation and migration. These findings for the first time demonstrates that TRPM7 (1) activates a previously unrecognized STAT3→ALDH1 pathway, and (2) promotes the induction of ALDH1 activity in glioma cells.
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影响因子：
5.5
作者：
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通讯作者：
Ouadid-Ahidouch, Halima
影响因子：
11.2
作者：
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3.7
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作者：
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Miyatake S
影响因子：
4.4
作者：
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通讯作者：
Ansari, NH