Targeting dual specificity protein kinase TTK attenuates tumorigenesis of glioblastoma.

Jia Wang,Hao Liu,Minxue Lian,Shuo Yu,Zhong Deng,Hai Yu,Maode Wang,Wanfu Xie,Yuchen Xie,Ning Wang,Xiaobin Bai

doi:10.18632/oncotarget.23152

Abstract

Accumulating evidence has proved that glioma stem-like cells (GSCs) are responsible for tumorigenesis, treatment resistance, and subsequent tumor recurrence in glioblastoma (GBM). In this study, we identified dual specificity protein kinase TTK (TTK) as the most up-regulated and differentially expressed kinase encoding genes in GSCs. Functionally, TTK was essential for in vitro clonogenicity and in vivo tumor propagation in GSCs. Clinically, TTK expression was highly enriched in GBM, moreover, was inversely correlated with a poor prognosis in GBM patients. Mechanistically, mitochondrial fission regulator 2 (MTFR2) was identified as one of the most correlated genes to TTK and transcriptionally regulated TTK expression via activation of TTK promoter. Collectively, MTFR2-dependent regulation of TTK plays a key role in maintaining GSCs in GBM and is a potential novel druggable target for GBM.

Highlights

Glioblastoma (GBM) is the most common intraparenchymal and lethal brain cancer and patients are left behind without any curable therapy to date [1,2,3]
To identify the functional role of TTK in GBM, an bioinformatics analysis based on the microarray database published in 2013 [16] was performed and the results indicated that TTK was one of the most elevated kinaseencoding genes in glioma stem-like cells (GSCs)-containing cell lines when compared with normal human astrocyte cells (Figure 1A)
We found that TTK expression was dramatically up-regulated in all the 4 subgroups of GBM according to TCGA database compared to the non-tumor tissue (Figure 1B, Supplementary Figure 1)

Summary

Introduction

Glioblastoma (GBM) is the most common intraparenchymal and lethal brain cancer and patients are left behind without any curable therapy to date [1,2,3]. Recent studies indicates that elevated TTK expression leads to tumorigenesis and poor prognosis in multiple types of malignant cancer, including gastric cancer, pancreatic cancer, breast cancer and liver cancer and bladder cancer, et al [10,11,12,13,14]. It is ambiguous about expression and functions of TTK in GBM, especially in GSCs. the up-stream regulating mechanism of TTK still remains unclear. Detailed studies focusing on the expression, function, and regulation mechanism of TTK in GBM and GSCs are needed

Methods

Results

Conclusion