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Low-Dose Endothelial-Monocyte-Activating Polypeptide-II Induced Autophagy by Down-Regulating miR-20a in U-87 and
Jiajia Chen1, Libo Liu1, Yunhui Liu2
1Department of Neurobiology, College of Basic Medicine, China Medical UniversityShenyang, China; Institute of Pathology and Pathophysiology, China Medical UniversityShenyang, China.
Abstract:
Preliminary studies have shown that endothelial-monocyte-activating polypeptide-II (EMAP-II) induces autophagy and inhibits the viability of glioma cells via an unknown molecular mechanism. This study explored the possible mechanisms associated with EMAP-II-induced autophagy in glioma cells by regulation of the expression of microRNA-20a (miR-20a). EMAP-II effectively inhibited the viability, migration and invasion of human U-87 and U-251 glioma cells. EMAP-II also up-regulated the expression level of autophagy biomarker microtubule-associated protein one light chain 3 (LC3)-II/I, autophagy related gene ATG7 and ATG5, but down-regulated autophagy substrate P62/SQSTM1 protein expression. The expression levels of miR-20a decreased significantly after U-87 and U-251 cells were treated with EMAP-II. MiR-20a overexpression partly reversed the EMAP-II-induced up-regulation of LC3-II/I and down-regulation of P62/SQSTM1. MiR-20a had a negative regulatory effect on the expression of the proteins ATG7 and ATG5; which were also targets of miR-20a, as detected by a dual-luciferase reporter assay. In addition, both EMAP-II and miR-20a inhibition significantly reduced the viability, migration and invasion of U-87 and U-251 cells, and their combination showed a synergistic effect. Furthermore, nude mice carrying silencing-expressed miR-20a combined with EMAP-II treatment produced the smallest tumors and the highest survival. In summary, low-dose EMAP-II increased expression levels of ATG5 and ATG7 via down-regulation of the expression of miR-20a. This activated the autophagy pathway, thereby significantly inhibiting the viability, migration and invasion of U-87 and U-251 glioma cells. The combined treatment of EMAP-II with a miR-20a inhibitor showed a synergistic effect against glioma.
Insights
Endothelial-monocyte-activating polypeptide-II (EMAP-II) inhibits glioma cell growth by down-regulating microRNA-20a (miR-20a), activating autophagy. Combined EMAP-II and miR-20a inhibition shows synergistic anti-glioma effects.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Endothelial-monocyte-activating polypeptide-II (EMAP-II) is known to induce autophagy and inhibit glioma cell viability.
- The precise molecular mechanisms underlying EMAP-II's effects on glioma cells remain largely unknown.
Purpose of the Study:
- To investigate the role of microRNA-20a (miR-20a) in mediating EMAP-II-induced autophagy and its impact on glioma cell behavior.
- To explore the therapeutic potential of combined EMAP-II and miR-20a modulation in glioma treatment.
Main Methods:
- Human U-87 and U-251 glioma cells were treated with EMAP-II.
- Expression levels of autophagy markers (LC3-II/I, ATG7, ATG5, P62/SQSTM1) and miR-20a were analyzed.
- Dual-luciferase reporter assays were used to confirm miR-20a targets.
- In vivo studies were conducted using nude mice xenografts.
Main Results:
- EMAP-II inhibited glioma cell viability, migration, and invasion, while up-regulating autophagy markers (LC3-II/I, ATG7, ATG5) and down-regulating P62/SQSTM1.
- EMAP-II treatment led to a significant decrease in miR-20a expression.
- Overexpression of miR-20a partially reversed EMAP-II's effects on autophagy markers and ATG7/ATG5 expression.
- Combined EMAP-II and miR-20a inhibition demonstrated synergistic anti-glioma effects in vitro and in vivo, with reduced tumor growth and increased survival in mice.
Conclusions:
- EMAP-II activates autophagy in glioma cells by down-regulating miR-20a, which in turn increases ATG5 and ATG7 expression.
- This EMAP-II/miR-20a/autophagy pathway significantly inhibits glioma cell viability, migration, and invasion.
- Combined therapeutic targeting of EMAP-II and miR-20a presents a promising synergistic strategy for glioma treatment.
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