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Published on: October 4, 2019
miR-637 Prevents Glioblastoma Progression by Interrupting ZEB2/WNT/β-catenin Cascades
Wei Wang1, Zilong Zhao1, Shuai Han1
1Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People's Republic of China.
Abstract:
Glioblastomas (GBMs) are the most frequent primary malignancies in the central nervous system. Aberrant activation of WNT/β-catenin signaling pathways is critical for GBM malignancy. However, the regulation of WNT/β-catenin signaling cascades remains unclear. Presently, we observed the increased expression of ZEB2 and the decreased expression of miR-637 in GBM. The expression of miR-637 was negatively correlated with ZEB2 expression. miR-637 overexpression overcame the ZEB2-enhanced cell proliferation and G1/S phase transition. Besides, miR-637 suppressed the canonical WNT/β-catenin pathways by targeting WNT7A directly. Gain- and loss-of-function experiments with U251 mice demonstrated that miR-637 inhibited cell proliferation and arrested the G1/S phase transition, leading to tumor growth suppression. The collective findings suggest that ZEB2 and WNT/β-catenin cascades merge at miR-637, and the ectopic expression of miR-637 disturbs ZEB2/WNT/β-catenin-mediated GBM growth. The findings provide new clues for improving β-catenin-targeted therapy against GBM.
Insights
Glioblastoma growth is suppressed by miR-637, a microRNA that targets WNT7A and inhibits the WNT/β-catenin pathway. This finding offers new therapeutic strategies for glioblastoma (GBM).
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Signaling
Background:
- Glioblastomas (GBMs) are aggressive primary brain tumors.
- Aberrant WNT/β-catenin signaling is crucial for GBM malignancy.
- Regulation of WNT/β-catenin cascades in GBM is not fully understood.
Purpose of the Study:
- To investigate the role of miR-637 and ZEB2 in GBM.
- To elucidate the regulatory mechanisms of WNT/β-catenin signaling in GBM.
- To explore miR-637 as a potential therapeutic target for GBM.
Main Methods:
- Analysis of ZEB2 and miR-637 expression in GBM samples.
- In vitro and in vivo gain- and loss-of-function experiments using U251 cells and mice.
- Luciferase reporter assays to confirm direct targeting of WNT7A by miR-637.
Main Results:
- GBM tissues exhibited increased ZEB2 and decreased miR-637 expression.
- miR-637 overexpression suppressed ZEB2-induced cell proliferation and G1/S phase transition.
- miR-637 directly targeted WNT7A, inhibiting the WNT/β-catenin pathway.
- In vivo studies confirmed miR-637's tumor suppressive effects in GBM.
Conclusions:
- ZEB2 and WNT/β-catenin pathways converge at miR-637 in GBM.
- Ectopic miR-637 expression inhibits GBM growth by disrupting ZEB2/WNT/β-catenin signaling.
- miR-637 represents a promising therapeutic target for β-catenin-targeted GBM treatment.
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