Microrchidia family CWtype zinc finger 2 promotes the proliferation, invasion, migration and epithelialmesenchymal transition of glioma by regulating PTEN/PI3K/AKT signaling via binding to Nmyc downstream regulated gene 1 promoter.
Int J Mol Med
; 49(2)2022 Feb.
Article
em En
| MEDLINE
| ID: mdl-34913078
ABSTRACT
Glioma is a common malignant tumor of the central nervous system with high incidence and mortality. The present study aimed to investigate the role of Microrchidia family CWtype zinc finger 2 (MORC2) in the development of glioma. Firstly, MORC2 expression was detected in several glioma cell lines (U251, SHG44, LN229 and T98G). Following MORC2 silencing, cell proliferation was evaluated using the Cell Counting Kit8 assay and the expression of proliferationrelated proteins was assessed via immunofluorescence staining or western blotting. Cell invasion and migration were assessed using transwell and wound healing assays, respectively. Western blotting and immunofluorescence staining were employed to determine the expression of epithelialmesenchymal transition (EMT)associated proteins. The protein expression of Nmyc downstream regulated gene 1 (NDRG1) and PTEN/PI3K/AKT signaling was determined with western blot analysis. Then, the luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were employed to evaluate the binding between MORC2 and NDRG1 promoter. Subsequently, cellular functional experiments were performed to assess the effects of NDRG1 on the progression of glioma after NDRG1 and MORC2 overexpression. In addition, tumorbearing experiments were conducted using a U251 tumorbearing nude mice model to detect tumor growth. The expression of proliferation (proliferating cell nuclear antigen, cyclindependent kinase 2 and cyclin E1), migration [matrix metalloproteinase (MMP)2 and MMP9], EMT (Ecadherin, Ncadherin and Vimentin) and PTEN/PI3K/AKT signaling proteins in tumor tissues was examined with immunohistochemistry assay or western blotting. Results revealed that MORC2 was notably unregulated in glioma cells compared with the normal human astrocyte. Lossfunction of MORC2 inhibited the proliferation, invasion, migration and EMT of glioma cells. Importantly, MORC2 silencing upregulated NDRG1 expression and inactivated PTEN/PI3K/AKT signaling. Additionally, the luciferase reporter and ChIP assays confirmed that MORC2 could bind to the NDRG1 promoter. NDRG1 upregulation suppressed the progression of glioma and these effects were partially reversed by MORC2 overexpression. Results of tumorbearing experiments suggested that gainfunction of NDRG1 inhibited tumor growth and downregulated the expression of proliferation, migration and EMTrelated proteins in tumorous tissue in U251 tumorbearing mice, which was partially counteracted after MORC2 overexpression. In addition, MORC2 overexpression abrogated the inhibitory effect of NDRG1 on PTEN/PI3K/AKT signaling. In summary, MORC2 promoted the progression of glioma by inactivation of PTEN/PI3K/AKT signaling via binding to NDRG1 promoter, providing a novel and potent target for the treatment of glioma.
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Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Transdução de Sinais
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Movimento Celular
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Regiões Promotoras Genéticas
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Proteínas de Ciclo Celular
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Peptídeos e Proteínas de Sinalização Intracelular
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Transição Epitelial-Mesenquimal
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Glioma
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article