MerTK mediates STAT3-KRAS/SRC-signaling axis for glioma stem cell maintenance
MerTK mediates STAT3-KRAS/SRC-signaling axis for glioma stem cell maintenance
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DOI：
10.1080/21691401.2018.1452022
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发表时间：
2018-01-01
影响因子：
5.8
通讯作者：
Lee, Su-Jae
中科院分区：
文献类型：
--
作者：
Eom, Hyojin;Kaushik, Neha;Lee, Su-Jae
受体酪氨酸激酶Mer(MerTK)在多形性胶质母细胞瘤(GBM)中的表达高于其正常对照，与脑肿瘤的发生密切相关。阐明MerTK诱导侵袭性的潜在机制将导致改善患者对化疗药物的反应的新策略。体外和体内实验检测肿瘤干细胞维持(CSC)在MerTK相关侵袭中的作用。在这篇文章中，我们证明了除了GBM细胞外，MerTK在GBM干细胞样细胞中也上调，并与体内脑肿瘤的浸润性增加有关。沉默MerTK抑制了患者来源的GBM干细胞的自我更新。MerTK参与CSC维持的信号机制在很大程度上还不清楚。分子分析表明，信号转导和转录激活因子3(STAT3)-Kirsten大鼠肉瘤病毒癌基因同源基因(KRAS)和原癌基因酪氨酸蛋白激酶SRC轴的高表达支持MerTK诱导的GBM球体中CSC的维持。此外，短发夹状RNA介导的MerTK基因敲除有效地阻止了小鼠异种移植瘤的侵袭性和N-钙粘素的表达。总而言之，我们的结果揭示了MerTK在CSC维护中的关键功能。考虑到MerTK在健康脑细胞中表达的基础水平较低，将MerTK作为治疗靶点的评估将促进对GBM更好的治疗方法的研究。
Receptor tyrosine kinase Mer (MerTK) has been shown to be highly expressed in Glioblastoma multiforme (GBM) in comparison to its healthy counterpart and is implicated in brain tumorigenesis. Clarifying the underlying mechanism of MerTK induced invasiveness would result in novel strategies to improve patient's response to chemotherapeutics. In vitro and in vivo assays were performed to examine the functional role of cancer stem sell (CSC) maintenance in MerTK associated invasiveness. In this article, we demonstrate that apart from GBM cells, MerTK is also upregulated in GBM stem-like cells and associated with an increased infiltrative potential of brain tumors in vivo. Silencing of MerTK suppressed the self-renewal of patient-derived GBM stem-like cells. The signaling mechanisms by which MerTK contributes to CSC maintenance have largely been obscure. Molecular analyses revealed that high expression of the signal transducer and activator of transcription 3 (STAT3)- Kirsten rat sarcoma viral oncogene homolog (KRAS) and proto-oncogene tyrosine-protein kinase SRC axis supports MerTK-induced CSC maintenance in GBM spheroids. Furthermore, a short-hairpin RNA-mediated MerTK knockdown effectively blocked invasiveness and N-cadherin expression in mouse xenografts. Collectively, our results uncover a critical function of MerTK in CSC maintenance. Considering the low basal level of MerTK expression in healthy brain cells, evaluation of MerTK as a therapeutic target should advance the research into better therapeutics for GBM.