MET Signaling Regulates Glioblastoma Stem Cells

Joo, Kyeung Min; Jin, Juyoun; Kim, Eun‐Hee; Kim, Kang Ho; Kim, Yonghyun; Kang, Bong Gu; Kang, Youn Jung; Lathia, Justin D.; Cheong, Kwang Ho; Song, Paul H.; Kim, Hyunggee; Seol, Ho Jun; Kong, Doo Sik; Lee, Jung Il; Rich, Jeremy; Lee, Jeongwu; Nam, Do Hyun

doi:10.1158/0008-5472.can-11-3760

Cited by 143 publications

(154 citation statements)

References 48 publications

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“…[29][30][31] EGFR, MET, PDGFR, and miRNAs have been implicated in the regulation of GSC functions. [32][33][34][35][36][37][38][39][40] This study identifies for the first time miR-134 as a critical RTK-regulated tumor suppressive hub that targets KRAS and STAT5B and mediates RTK and RTK inhibitor effects on GBM malignancy.…”

mentioning

confidence: 89%

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Zhang

Mueller

et al. 2014

Cell Death Differ

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Receptor tyrosine kinases (RTKs) are co-deregulated in a majority of glioblastoma (GBM), the most common and most deadly brain tumor. We show that the RTKs MET, EGFR, and PDGFR regulate microRNA-134 (miR-134) in GBM. We find that miR-134 is downregulated in human tumors and cancer stem cells and that its expression inversely correlates with the activation of MET, EGFR, and PDGFR. We demonstrate that miR-134 inhibits cancer cell and stem-cell proliferation, survival, and xenograft growth, as well as cancer stem-cell self-renewal and stemness. We identify KRAS and STAT5B as targets of miR-134, and establish molecular and functional links between RTKs, miR-134, KRAS/STAT5B and malignancy in vitro and in vivo. We show that miR-134 induction is required for the anti-tumor effects of RTK inhibitors. We also uncover the molecular pathways through which RTKs regulate miR-134 expression and demonstrate the involvement of MAPK signaling and the KLF4 transcription factor. We therefore identify miR-134 as a novel RTK-regulated tumor-suppressive hub that mediates RTK and RTK-inhibitor effects on GBM malignancy by controlling KRAS and STAT5B. Cell Death and Differentiation (2014) 21, 720-734; doi:10.1038/cdd.2013; published online 17 January 2014 microRNAs (miRNAs) regulate a wide variety of physiological and pathological processes. 1-3 miRNAs modulate protein expression by binding to the 3 0 untranslated region (3 0 UTR) of target mRNA and promoting RNA degradation and/or inhibiting translation. Single miRNAs can regulate multiple molecules, highlighting a powerful mechanism for the regulation of redundant and cross-talking signal transduction pathways. 4 miRNA dysregulation is a common feature of neoplasia and numerous miRNAs have been characterized as oncogenes or tumor suppressors in many cancers including in glioblastoma (GBM). 3,[5][6][7][8][9][10][11] microRNA-134 (miR-134) has been implicated in the regulation of physiological and developmental processes. It was shown to promote mouse embryonic stem-cell differentiation, dendritogenesis, and stage-specific cortical development. 12-17 miR-134 is downregulated by SIRT1 and involved in synaptic plasticity and memory formation. 18 miR-134 expression is regulated by MEF2 in dendritogenesis 14 and GBM. 19 GBM is the most common and most deadly primary malignant brain tumor. 20,21 The Cancer Genome Atlas and other studies have shown that aberrant expression or activation of the receptor tyrosine kinases (RTKs) EGFR, MET, and PDGFR occurs in a majority of GBM and correlates with poor prognosis. 22 Importantly, multiple RTKs are co-activated in the same GBM tumors and tumor cells. 23,24 KRAS, STAT3, and STAT5 are activated by RTKs and mediate their oncogenic effects. [25][26][27][28] The failure of current treatments for GBM is arguably due to the presence in the tumors of GBM stem cells (GSCs) that are resistant to radioand chemo-therapy and capable of maintaining and propagating the tumors. 29-31 EGFR, MET, PDGFR, and miRNAs have been implicated in the regulation of GSC f...

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confidence: 89%

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Zhang

Mueller

et al. 2014

Cell Death Differ

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“…In accordance with these observations, we detected an upregulation of signaling through MET in the HGG-02 cells, which may partially compensate for the downregulation of EGFR signaling caused by the loss of EGFR gene copy. MET overexpression has been associated with a shorter survival time and poor response (20), and it has been suggested that MET activation is required for the acquisition of the glioblastoma cancer stem cell phenotype (21). Furthermore, upregulated phosphorylation of RON, the MSP receptor, may indicate another compensatory mechanism in HGG-02 cells.…”

Section: Discussionmentioning

confidence: 99%

EGFR signaling in the HGG-02 glioblastoma cell line with an unusual loss of EGFR gene copy

et al. 2013

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Abstract. Epidermal growth factor receptor (EGFR) gene amplification and the overexpression of EGFR are described as common features of glioblastoma multiforme (GBM). Nevertheless, we previously reported the loss of EGFR gene copy in a GBM specimen from a patient with an unusually favorable course of the disease, and the HGG-02 cell line with this aberration was successfully derived from this tumor. Here, we present a detailed analysis of changes in gene expression and cell signaling in the HGG-02 cell line; the GM7 reference cell line with a standard EGFR gene copy number derived from a very aggressive GBM was used as a control. We confirmed the downregulation of EGFR expression and signaling in HGG-02 cells using different methods (RTK analysis, gene profiling and RT-PCR). Other changes that may have contributed to the non-aggressive phenotype of the primary tumor were identified, including the downregulated phosphorylation of the Axl and Trk receptors, as well as increased activity of JNK and p38 kinases. Notably, differences in PDGF signaling were detected in both of these cell lines; HGG-02 cells preferentially expressed and signaled through PDGFRα, and PDGFRβ was strongly overexpressed and phosphorylated in the GM7 reference cell line. Using expression profiling of cancer-related genes, we revealed the specific profile of HGG-02 cells that included upregulated tumor-suppressors as well as downregulated genes associated with the extracellular matrix. This study represents the first comprehensive analysis of gene expression and cell signaling in glioblastoma cells with lower EGFR gene

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“…120 In fact, inhibition of c-Met signaling in GBM stem cells disrupts tumor growth and invasiveness both in vivo and in vitro. 95 Attempts at EGFR inhibition in GBM often induce high levels of c-Met activation as a mechanism of anti-EGFR resistance, further potentiating c-Met as a therapeutic target. 96 Inhibition of c-Met expression using chimeric transgenes decreases GBM tumor growth and malignancy, 2 including decreased angiogenesis as well as increased apoptosis in vivo.…”

Section: C-mesenchymal-epithelial Transitionmentioning

confidence: 99%

Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

Womeldorff¹,

Gillespie²,

Jensen³

2014

FOC

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Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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MET Signaling Regulates Glioblastoma Stem Cells

Cited by 143 publications

References 48 publications

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

EGFR signaling in the HGG-02 glioblastoma cell line with an unusual loss of EGFR gene copy

Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

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