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EBioMedicine ; 52: 102651, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32062354


BACKGROUND: Glioma has a poor prognosis, and is the most common primary and lethal primary malignant tumor in the central nervous system. Retinoic acid receptor-related orphan receptor A (RORA) is a member of the ROR subfamily of orphan receptors and plays an anti-tumor role in several cancers. METHODS: A cell viability assay, the Edu assay, neurosphere formation assay, and xenograft experiments were used to detect the proliferative abilities of glioma cell line, glioma stem cells (GSCs). Western blotting, ELISAs, and luciferase reporter assays were used to detect the presence of possible microRNAs. FINDINGS: Our study found for the first time that RORA was expressed at low levels in gliomas, and was associated with a good prognosis. RORA overexpression inhibited the proliferation and tumorigenesis of glioma cell lines and GSCs via inhibiting the TNF-α mediated NF-κB signaling pathway. In addition, microRNA-18a had a promoting effect on gliomas, and was the possible reason for low RORA expression in gliomas. INTERPRETATION: RORA may be a promising therapeutic target in the treatment of gliomas.

EBioMedicine ; 48: 36-48, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31631037


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.  :  .

J Pathol ; 249(1): 26-38, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30953361


Mesenchymal glioblastoma (GBM) is the most aggressive subtype of GBM. Our previous study found that neurotrophic factor prosaposin (PSAP) is highly expressed and secreted in glioma and can promote the growth of glioma. The role of PSAP in mesenchymal GBM is still unclear. In this study, bioinformatic analysis, western blotting and RT-qPCR were used to detect the expression of PSAP in different GBM subtypes. Human glioma cell lines and patient-derived glioma stem cells were studied in vitro and in vivo, revealing that mesenchymal GBM expressed and secreted the highest level of PSAP among four subtypes of GBM, and PSAP could promote GBM invasion and epithelial-mesenchymal transition (EMT)-like processes in vivo and in vitro. Bioinformatic analysis and western blotting showed that PSAP mainly played a regulatory role in GBM invasion and EMT-like processes via the TGF-ß1/Smad signaling pathway. In conclusion, the overexpression and secretion of PSAP may be an important factor causing the high invasiveness of mesenchymal GBM. PSAP is therefore a potential target for the treatment of mesenchymal GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mol Inform ; 35(6-7): 262-7, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27492240


Rho-kinase dimerization is essential for its kinase activity and biological function; disruption of the dimerization has recently been established as a new and promising therapeutics strategy for cerebrovascular malformation (CM). Based on Rho-kinase dimer crystal structure we herein combined in silico analysis and in vitro assay to rationally derive self-inhibitory peptides from the dimerization interface. Three peptides namely Hlp1, Hlp2 and Hlp3 were successfully designed that have potential capability to rebind at the dimerization domain of Rho-kinase. Molecular dynamics (MD) simulations revealed that these peptides are helically structured when bound to Rho-kinase, but exhibit partially intrinsic disorder in unbound state. Binding free energy (BFE) analysis suggested that the peptides have a satisfactory energetic profile to interact with Rho-kinase. The computational findings were then substantiated by fluorescence anisotropy assays, conforming that the helical peptides can bind tightly to Rho-kinase with affinity KD at micromolar level. These designed peptides are considered as lead molecular entities that can be further modified and optimized to obtain more potent peptidomimetics as self-competitors to disrupt Rho-kinase dimerization in CM.

Inibidores de Proteínas Quinases/química , Quinases Associadas a rho/química , Avaliação Pré-Clínica de Medicamentos , Polarização de Fluorescência , Malformações Arteriovenosas Intracranianas/tratamento farmacológico , Malformações Arteriovenosas Intracranianas/enzimologia , Simulação de Dinâmica Molecular , Peptídeos/química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Termodinâmica