Activated STAT3 Regulates Hypoxia-Induced Angiogenesis and Cell Migration in Human Glioblastoma

Kang, Sung Ho; Yu, Mi Ok; Park, Kyung Jae; Gil, Sung; Park, Dong Hyuk; Chung, Yong Gu

doi:10.1227/neu.0b013e3181f1c0cd

Cited by 60 publications

(42 citation statements)

References 47 publications

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“…Preparation of whole-cell lysates and western blot analysis was done as described previously [22]. The blots were probed with anti-AEG-1 (Invitrogen), anti-p-Akt, anti-Akt, and anti-Bcl-2 (Cell signaling Technology, Irvine, CA, USA) and with anti-beta actin (BioVision Research Products, Mountain View, CA, USA) antibodies.…”

Section: Protein Analysismentioning

confidence: 99%

Expression of astrocyte elevated gene-1 (AEG-1) in human meningiomas and its roles in cell proliferation and survival

Park

Song

et al. 2014

J Neurooncol

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Astrocyte elevated gene-1 (AEG-1) has recently been proposed to be involved in tumor development, invasion, and metastasis in several human cancers. However, the functional importance of AEG-1 expression in human meningioma has not been determined. We investigate the level of AEG-1 expression by quantitative reverse transcription PCR, immunohistochemistry analysis, and western blotting in various human meningioma tissues and cells. To determine the suppressive effect of AEG-1 on meningioma progression, we inhibited AEG-1 expression using small interfering RNA and examined cell proliferation, apoptosis, colony formation and tumorigenicity in a mouse xenograft model. AEG-1 expression was frequently elevated at both mRNA and protein levels in meningioma tumor tissues and in meningioma-derived cells as well. This elevation was more commonly observed in high-grade tumors than in benign ones. The knockdown of AEG-1 led to a decrease in overall cell proliferation, as well as anchorage-independent growth of malignant meningioma. In addition, apoptotic cell death occurred in AEG-1 depleted meningioma cells through p-Akt and Bcl-2 suppression. Furthermore, a mouse xenograft meningioma model showed that inhibition of AEG-1 expression significantly decreased tumor growth. Altogether, these data show that the elevation of AEG-1 contributes to the malignant progression of meningiomas, suggesting that AEG-1 could be a novel therapeutic target against human meningiomas.

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Section: Protein Analysismentioning

confidence: 99%

Expression of astrocyte elevated gene-1 (AEG-1) in human meningiomas and its roles in cell proliferation and survival

Park

Song

et al. 2014

J Neurooncol

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“…As many research showed including ours, when cells are under hypoxia stimuli, levels of p-STAT3 and miR-34a will be upregulated and downregulated respectively [52,53]. In our study, Western blot and RT-PCR results showed resveratrol inhibited hypoxia-induced activation of STAT3 and downregulation of miR-34a, which indicates p-STAT3 and miR-34a might involve in regulation of resveratrol in hypoxia-induced migration and invasion and its effect is both time-and dosedependent.…”

Section: Discussionmentioning

confidence: 67%

Resveratrol inhibits hypoxia-induced glioma cell migration and invasion by the p-STAT3/miR-34a axis

Wang¹,

Han²,

Zhang³

2016

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Hypoxia promotes aggressiveness, angiogenesis and resistance in glioma. It has been reported that resveratrol has strong anti-tumor ability and can inhibit migration and invasion of varieties of tumor including glioma. However, whether resveratrol inhibits hypoxia-induced migration and invasion of glioma cells is still unknown. In this study, we found glioma U87 and U251 cells migration and invasion was reduced by resveratrol under hypoxia condition and higher doses led to stronger block, while proliferation of U87 and U251 cells was hardly effected. Mechanically, hypoxia-induced upregulation of phosphorylated signal transducer and activator of transcription 3(p-STAT3) was blocked by resveratrol. MicroRNA-34a (miR-34a) is a tumor suppressor whose promoter region has a conserved STAT3-binding site and can be negatively regulated by STAT3. Interestingly, miR-34a was downregulated under hypoxia but upregulated by resveratrol which was perhaps relevant to changes in level of p-STAT3. The effect of resveratrol on p-STAT3 and miR-34a was both time-and dose-dependent. Summarizing, resveratrol inhibits hypoxia-induced migration and invasion possibly via p-STAT3/miR-34a axis and this effect is both time-and dose-dependent.

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“…Anterior gradient protein 2(AGR2) induced by HIF-1 is overexpressed at both gene and protein levels in many malignant tumors, including GBM, which is vitally important in promoting angiogenesis. Since AGR2 shRNA can manifest the effect of suppressing this pro-angiogenesis in GBM cell lines, this mechanism has been proposed to enhance antiangiogenic therapies [59][60][61]. Plexin-A4 combined with the VEGF-2 receptor is shown to enhance the VEGF-induced signal transduction.…”

Section: New Anti-angiogenic Regulator Factorsmentioning

confidence: 99%

Recent advance in molecular angiogenesis in glioblastoma: the challenge and hope for anti-angiogenic therapy

Zhang

et al. 2015

Brain Tumor Pathol

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Glioblastoma (GBM) is the most highly malignant brain tumor in the human central nerve system. In this paper, we review new and significant molecular findings on angiogenesis and possible resistance mechanisms. Expression of a number of genes and regulators has been shown to be upregulated in GBM microvessel cells, such as interleukin-8, signal transducer and activator of transcription 3, Tax-interacting protein-1, hypoxia induced factor-1 and anterior gradient protein 2. The regulator factors that may strongly promote angiogenesis by promoting endothelial cell metastasis, changing the microenvironment, enhancing the ability of resistance to anti-angiogenic therapy, and that inhibit angiogenesis are reviewed. Based on the current knowledge, several potential targets and strategies are proposed for better therapeutic outcomes, such as its mRNA interference of DII4-Notch signaling pathway and depletion of b1 integrin expression. We also discuss possible mechanisms underlying the resistance to anti-angiogenesis and future directions and challenges in developing new targeted therapy for GBM.

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Activated STAT3 Regulates Hypoxia-Induced Angiogenesis and Cell Migration in Human Glioblastoma

Abstract: STAT3 plays an important role in glioblastoma angiogenesis and migration triggered by hypoxia. Therefore, STAT3 might be a target for control of pseudopalisading necrosis and angiogenesis in glioblastoma.

Cited by 60 publications

References 47 publications

Expression of astrocyte elevated gene-1 (AEG-1) in human meningiomas and its roles in cell proliferation and survival

Expression of astrocyte elevated gene-1 (AEG-1) in human meningiomas and its roles in cell proliferation and survival

Resveratrol inhibits hypoxia-induced glioma cell migration and invasion by the p-STAT3/miR-34a axis

Recent advance in molecular angiogenesis in glioblastoma: the challenge and hope for anti-angiogenic therapy

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