Overexpression of Limb-Bud and Heart (LBH) promotes angiogenesis in human glioma via VEGFA-mediated ERK signalling under hypoxia

Jiang, Yang; Zhou, Jinpeng; Zou, Dan; Hou, Dianqi; Zhang, Haiying; Zhao, Junshuang; Li, Long; Hu, Jiangfeng; Zhang, Ye

doi:10.1016/j.ebiom.2019.09.037

Cited by 53 publications

(46 citation statements)

References 52 publications

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“…Studies have shown that the mechanism of microvessel proliferation and basal membrane degradation in other diseases, such as cancers and strokes, involves the JAK2/ STAT3, IL-6/JAK2/STAT3, and MMP-9 pathways, which regulate the progression of tumor metastasis [9][10][11]. Currently, the pathways involved in hypoxia-mediated microvessel proliferation and basal membrane degradation have not been reported, except the IL-6/JAK2/STAT3/MMP-9 pathway in our study [37][38][39].…”

Section: Discussionmentioning

confidence: 99%

“…With the STAT3 inhibitor, many factors should be analyzed. Firstly, it is well established that regulation of erythropoiesis and vasculogenesis is an adaption to hypoxia in the healthy body [6][7][8][9]. On the one hand, previous studies showed that hematopoietic and endothelial cell lineages share common progenitors that affect the proliferation and differentiation of bone marrow-derived or umbilical cord blood-derived endothelial progenitor cells, which in turn promote angiogenesis [56,57].…”

Section: Ch + Dmso Ch + Inhibitor Ch Controlmentioning

confidence: 99%

“…e prevalence of CH at high altitude is increased by 10% in Peruvian Andes at an altitude of about 2500 m and by 17.8% in Chinese Han men who migrated to the Qinghai-Tibetan plateau at an altitude of 3700-5000 m [2,4,5]. Previous studies showed that CH arises due to the excessive production of erythrocytes, which increases the blood viscosity causing blood flow retardation leading to exacerbated hypoxic-ischemic injury and eventually angiogenesis and basal membrane (BM) degradation of the blood vessel in tissues [6][7][8][9][10]. In addition, in a previous study, we showed that patients with CH frequently exhibit an erythematic facial color with marked congestion of the mucosa and conjunctiva as a result of the formation of new vessels and that CH is associated with changes in bone marrow MVD [6].…”

Section: Introductionmentioning

confidence: 99%

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Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

Zhu

Yang

et al. 2020

BioMed Research International

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Chronic hypoxia (CH) is characterized by long-term hypoxia that is associated with microvessel proliferation and basal membrane (BM) degradation in tissues. The IL-6/JAK2/STAT3/MMP-9 pathway has been described in a variety of human cancers and plays an essential role in microvessel proliferation and BM degradation. Therefore, this study investigated the role of the IL-6/JAK2/STAT3/MMP-9 pathway in hypoxia-mediated microvessel proliferation and BM degradation in the rat bone marrow. Eighty pathogen-free Sprague Dawley male rats were randomly divided into four groups (20 per group)—control group, CH group (exposed to hypoxia in a hypobaric chamber at a simulated altitude of 5000 m for 28 d), CH + STAT3 inhibitor group (7.5 mg/kg/d), and CH + DMSO group. Microvessel density (MVD) and BM degradation in the bone marrow were determined by immunofluorescence staining and transmission electron microscopy. Serum IL-6 levels were assessed by enzyme-linked immunosorbent assay (ELISA), and the levels of P-JAK2, P-STAT3, and MMP-9 were assessed by western blot analysis and real-time reverse transcription PCR (RT-PCR). Hypoxia increased serum IL-6 levels, which in turn increased JAK2 and STAT3 phosphorylation, which subsequently upregulated MMP-9. Overexpression of MMP-9 significantly promoted the elevation of MVD and BM degradation. Inhibition of STAT3 using an inhibitor, SH-4-54, significantly downregulated MMP-9 expression and decreased MVD and BM degradation. Surprisingly, STAT3 inhibition also decreased serum IL-6 levels and JAK2 phosphorylation. Our results suggest that the IL-6/JAK2/STAT3/MMP-9 pathway might be related to CH-induced microvessel proliferation and BM degradation in the bone marrow.

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Section: Discussionmentioning

confidence: 99%

Section: Ch + Dmso Ch + Inhibitor Ch Controlmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

Zhu

Yang

et al. 2020

BioMed Research International

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“…The preparation of GCM has been previously described [24]. Briefly, we used serum-free DMEM/F12 to wash GSCs three times, followed by culturing the GSCs for 24 h. The medium was then collected and centrifuged at 3000×g for 15 min at 4°C to remove GSCs and debris.…”

Section: Preparation Of the Glioma Conditioned Medium (Gcm)mentioning

confidence: 99%

The U2AF2 /circRNA ARF1/miR-342–3p/ISL2 feedback loop regulates angiogenesis in glioma stem cells

Jiang

Zhou

Zhao

et al. 2020

J Exp Clin Cancer Res

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Background Glioma is the most common and lethal primary brain tumor in adults, and angiogenesis is one of the key factors contributing to its proliferation, aggressiveness, and malignant transformation. However, the discovery of novel oncogenes and the study of its molecular regulating mechanism based on circular RNAs (circRNAs) may provide a promising treatment target in glioma. Methods Bioinformatics analysis, qPCR, western blotting, and immunohistochemistry were used to detect the expression levels of ISL2, miR-342–3p, circRNA ARF1 (cARF1), U2AF2, and VEGFA. Patient-derived glioma stem cells (GSCs) were established for the molecular experiments. Lentiviral-based infection was used to regulate the expression of these molecules in GSCs. The MTS, EDU, Transwell, and tube formation assays were used to detect the proliferation, invasion, and angiogenesis of human brain microvessel endothelial cells (hBMECs). RNA-binding protein immunoprecipitation, RNA pull-down, dual-luciferase reporter, and chromatin immunoprecipitation assays were used to detect the direct regulation mechanisms among these molecules. Results We first identified a novel transcription factor related to neural development. ISL2 was overexpressed in glioma and correlated with poor patient survival. ISL2 transcriptionally regulated VEGFA expression in GSCs and promoted the proliferation, invasion, and angiogenesis of hBMECs via VEGFA-mediated ERK signaling. Regarding its mechanism of action, cARF1 upregulated ISL2 expression in GSCs via miR-342–3p sponging. Furthermore, U2AF2 bound to and promoted the stability and expression of cARF1, while ISL2 induced the expression of U2AF2, which formed a feedback loop in GSCs. We also showed that both U2AF2 and cARF1 had an oncogenic effect, were overexpressed in glioma, and correlated with poor patient survival. Conclusions Our study identified a novel feedback loop among U2AF2, cARF1, miR-342–3p, and ISL2 in GSCs. This feedback loop promoted glioma angiogenesis, and could provide an effective biomarker for glioma diagnosis and prognostic evaluation, as well as possibly being used for targeted therapy.

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“…In atherosclerotic, folic acid reduced atherosclerotic lesion through elevating DNA methyltransferase activity and expression, altering MCP1 and VEGF promoter methylation, and inhibiting MCP1 and VEGF expression [17]. The expression of VEGF was signi cant up-regulated in human glioma via [18,19].…”

Section: Introductionmentioning

confidence: 99%

miR-148a-3p inhibits DNMT1-mediated methylation of VEGF and promotes proliferation and invasion in glioma cells via the PI3K/Akt/eNOS signaling pathway

Huo

Chen

2020

Preprint

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Background: Abnormal DNA methylation in the promoter region of vascular endothelial growth factor (VEGF) has been observed in multiple types of cancer. Increasing evidence shows that miR-148a-3p is involved in the regulation of methylation. However, it is unclear how miR-148a-3p regulates VEGF methylation.Methods: Methylation-specific polymerase chain reaction (MSP) and bisulfate-sequencing PCR (BSP) were performed to detect the methylation level of the VEGF promoter region in glioma tissues and cell lines. Then, we used RT-qPCR to detect the expression of miR-148a-3p and VEGF in glioma tissues and cell lines. Human glioma U87 cells were transfected with miR-148a-3p mimic or a pcDNA3.1 overexpression vector of VEGF, and then, the proliferation, invasion and apoptosis of U87 cells were examined with cell counting kit-8 (CCK-8), Transwell assay and Flow cytometry, respectively. We next examined the relationship between DNA methyltransferase 1 (DNMT1) and miR-148a-3p with online prediction and luciferase reporter gene experiments. Furthermore, we also used Western blotting to detect the protein levels of VEGF, DNMT1, PI3K, Akt and eNOS.Results: Both miR-148a-3p and VEGF were significantly up-regulated, and the promoter methylation of VEGF was hypomethylation in glioma. Overexpression miR-148a-3p or VEGF promoted the proliferation and invasion of U87 cells and inhibited the apoptosis. Silencing VEGF inhibited U87 cells proliferation and invasion and induced the apoptosis. Furthermore, miR-148a-3p regulated DNMT1 at the post-transcriptional. Overexpression of DNMT1 mediated an increase in the methylation level of VEGF, which reduced the expression of VEGF in U87 cells. The opposite was exact when DNMT1 was silenced. We also observed that silencing VEGF inhibited the activation of the PI3K/Akt/eNOS pathway and induced U87 cell apoptosis.Conclusion: These results indicated that miR-148a-3p down-regulates VEGF methylation by targeting DNMT1 and promotes the proliferation, invasion of the glioma cell through the PI3K/Akt/eNOS pathway.

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Overexpression of Limb-Bud and Heart (LBH) promotes angiogenesis in human glioma via VEGFA-mediated ERK signalling under hypoxia

Cited by 53 publications

References 52 publications

Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

The U2AF2 /circRNA ARF1/miR-342–3p/ISL2 feedback loop regulates angiogenesis in glioma stem cells

miR-148a-3p inhibits DNMT1-mediated methylation of VEGF and promotes proliferation and invasion in glioma cells via the PI3K/Akt/eNOS signaling pathway

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