Dataset Information

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

ABSTRACT: BACKGROUND:Glioma is the most common primary malignant tumor in the central nervous system with frequent hypoxia and angiogenesis. Limb-Bud and Heart (LBH) is a highly conserved transcription cofactor that participates in embryonic development and tumorigenesis. METHODS:The conditioned media from LBH regulated human glioma cell lines and patient-derived glioma stem cells (GSCs) were used to treat the human brain microvessel endothelial cells (hBMECs). The function of LBH on angiogenesis were examined through methods of MTS assay, Edu assay, TUNEL assay, western blotting analysis, qPCR analysis, luciferase reporter assay and xenograft experiment. FINDINGS:Our study found for the first time that LBH was overexpressed in gliomas and was associated with a poor prognosis. LBH overexpression participated in the angiogenesis of gliomas via the vascular endothelial growth factor A (VEGFA)-mediated extracellular signal-regulated kinase (ERK) signalling pathway in human brain microvessel endothelial cells (hBMECs). Rapid proliferation of gliomas can lead to tissue hypoxia and hypoxia inducible factor-1 (HIF-1) activation, while HIF-1 can directly transcriptionally regulate the expression of LBH and result in a self-reinforcing cycle. INTERPRETATION:LBH may be a possible treatment target to break the vicious cycle in glioma treatment. ?: ?.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC6838451 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Jiang Yang Y Zhou Jinpeng J Zou Dan D Hou Dianqi D Zhang Haiying H Zhao Junshuang J Li Long L Hu Jiangfeng J Zhang Ye Y Jing Zhitao Z

EBioMedicine 20191017

<h4>Background</h4>Glioma is the most common primary malignant tumor in the central nervous system with frequent hypoxia and angiogenesis. Limb-Bud and Heart (LBH) is a highly conserved transcription cofactor that participates in embryonic development and tumorigenesis.<h4>Methods</h4>The conditioned media from LBH regulated human glioma cell lines and patient-derived glioma stem cells (GSCs) were used to treat the human brain microvessel endothelial cells (hBMECs). The function of LBH on angiog ...[more]

PMID: 31631037

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Project description:The limb-bud and heart (LBH) gene was reported to suppress nasopharyngeal carcinoma (NPC) progression in our previous study. Distant metastasis predominantly accounts for the unsatisfactory prognosis of NPC treatment, in which epithelial-mesenchymal transition (EMT) and tumor angiogenesis are of great significance. The roles of exosomes in mediating NPC progression have been highlighted in recent researches, and attempts have been made to explore the clinical application of NPC exosomes. Here we investigated the function of the LBH gene in NPC exosomes, and its potential mechanism. NPC xenografts were constructed, showing that vascular endothelial growth factor A (VEGFA) expression and neovascularity were attenuated by LBH overexpression, together with diminished EMT progression. NPC-derived exosomes were isolated, identified and applied for in vitro/in vivo experiments, and the exosomal distribution of LBH was elevated in exosomes derived from LBH-upregulated cells. Ectopic LBH, αB-crystallin (CRYAB) and VEGFA expression was induced by lentiviral infection or plasmid transfection to explore their functions in modulating EMT and angiogenesis in NPC. The addition of LBH+ NPC exosomes during a Matrigel plug assay in mice suppressed in vivo angiogenesis, and the treatment of human umbilical vein endothelial cells (HUVECs) with LBH+ NPC exosomes inhibited cellular proliferation, migration and tube formation. The interactions among LBH, CRYAB and VEGFA were confirmed by colocalization and fluorescence resonance energy transfer (FRET) assays, and extracellular VEGFA secretion from both HUVECs and NPC cells under the treatment with LBH+ NPC exosomes was diminished according to ELISA results. We concluded that exosomal LBH inhibits EMT progression and angiogenesis in the NPC microenvironment, and that its effects are partially implemented by modulation of VEGFA expression, secretion and related signaling. Thus, LBH could serve as a promising therapeutic target in VEGFA-focused NPC treatment.

Project description:BACKGROUND:Breast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear. METHODS:The prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model. RESULTS:ACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs. CONCLUSIONS:Our findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway. TRIAL REGISTRATION:Retrospectively registered.

Dataset Information

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

Publications

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

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