CircKIF4A promotes tumorogenesis of glioma by targeting miR-139-3p to activate Wnt5a signaling

Long-Wei Huo,Xiao-Bin Bai,Hu-Lin Zheng,Ya-Fei Wang,Mao-De Wang

doi:10.1186/s10020-020-00159-1

Abstract

BackgroundGlioma has the characteristics of high incidence and mortality, and is a common malignant tumor of the central nervous system. Circular RNAs (circRNAs) have been reported to play vital roles in progression of cancer including glioma, and circKIF4A is up-regulated in glioma tissues. However, its role and mechanisms in gliomas are unclear.MethodscircKIF4A and miR-139-3p were determined by qRT-PCR. Transwell assay, wound-healing assay, cell colony formation and flow cytometry were performed to measure cell invasion, migration, proliferation and apoptosis. Western blotting was used to evaluate Wnt/β-catenin pathway-related protein. Luciferase reporter assays confirmed the relationship among circKIF4A, miR-139-3p and Wnt5a. Sphere formation was performed to measure the ability of glioma-initiating cells (GICs) spheroid formation. A nude mouse xenograft model was established and immunohistochemical staining was used to detect Ki-67 and Wnt5a levels.ResultscircKIF4A and Wnt5a were up-regulated and miR-139-3p was down-regulated in both glioma cells and tissues. circKIF4A promoted Wnt5a expression by sponging miR-139-3p. Knockdown of circKIF4A inhibited the colony formation ability, migration and invasion, and promoted the apoptosis of glioma cells by regulating miR-139-3p. Knockdown of circKIF4A inhibited Wnt/β-catenin signaling pathway and proliferation-related signal via miR-139-3p. Furthermore, knockdown of circKIF4A or overexpression of miR-139 suppressed the ability of sphere formation of GICs and inhibitd Wnt/β-catenin signaling pathway and proliferation-related signal in GICs. Additionally, depletion of circKIF4A decreased the expression level of Wnt5a and Ki-67, inhibited tumorigenesis in xenograft modes.ConclusioncircKIF4A was overexpressed in glioma, and knockdown of circKIF4A suppressed glioma progression via miR-139-3p/Wnt5a axis. The results indicated that circKIF4A may be a potential target for clinical treatment of glioma.

Highlights

Glioma has the characteristics of high incidence and mortality, and is a common malignant tumor of the central nervous system
Results circKIF4A and Wnt5a are up-regulated and miR-139-3p is down-regulated in glioma cell lines and tissues To investigate the roles of circKIF4A, miR-139-3p and Wnt5a in glioma, we first detected the expression of circKIF4A, miR-139-3p and Wnt5a in 32 pairs of glioma and adjacent normal tissues
Spearman correlation analysis was performed to calculate the correlation among circKIF4A, miR-139-3p, and Wnt5a levels in glioma samples. circKIF4A was inversely correlated with miR-1393p expression and positively correlated with Wnt5a expression (Fig. 1d, e)

Summary

Introduction

Glioma has the characteristics of high incidence and mortality, and is a common malignant tumor of the central nervous system. GBM was found to be the most common malignant primary brain tumor, accounting for 16% of all primary brain tumors and 54% of all gliomas (Chuntova et al 2018), with high morbidity, high recurrence rate, high mortality and low cure rate (Chen et al 2018). Surgical techniques and adjuvant therapy have evolved over the decades, the treatment and prognosis of gliomas still face significant challenges (Tomiyama and Ichimura 2019). This undesirable result is due in part to the cell-autonomous functions of therapeutically resistant glioma-initiating cells (GICs) (Figueroa et al 2017). An in-depth study of the molecular mechanisms associated with glioma is of great value in the development of potential glioma targeted therapies

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Conclusion