MLK3 Is Associated With Poor Prognosis in Patients With Glioblastomas and Actin Cytoskeleton Remodeling in Glioblastoma Cells.

Yan Zhu,Zi-Chen Sun,Xiao-Yu Hou,Feng-Jiao Chen,Yong-Ping Wu,Jin-Min Sun

doi:10.3389/fonc.2020.600762

Yan Zhu, Zi-Chen Sun + Show 4 more

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https://doi.org/10.3389/fonc.2020.600762

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Abstract

Mixed lineage kinase 3 (MLK3) has been implicated in human melanoma and breast cancers. However, the clinical significance of MLK3 in human gliomas and the underlying cellular and molecular mechanisms remain unclear. We found that MLK3 proteins were highly expressed in high-grade human glioma specimens and especially prevalent in primary and recurrent glioblastoma multiforme (GBM). High levels of MLK3 mRNA were correlated with poor prognosis in patients with isocitrate dehydrogenase (IDH)-wild-type (wt) gliomas. Furthermore, genetic ablation of MLK3 significantly suppressed the migration and invasion abilities of GBM cells and disrupted actin cytoskeleton organization. Importantly, MLK3 directly bound to epidermal growth factor receptor kinase substrate 8 (EPS8) and regulated the cellular location of EPS8, which is essential for actin cytoskeleton rearrangement. Overall, these findings provide evidence that MLK3 upregulation predicts progression and poor prognosis in human IDH-wt gliomas and suggest that MLK3 promotes the migration and invasion of GBM cells by remodeling the actin cytoskeleton via MLK3-EPS8 signaling.

Highlights

Gliomas, one of the most prevalent forms of primary brain tumors, are classified into four grades in line with the World Health Organization (WHO) 2016 classification criteria [1]
Our findings provide the first evidence that Mixed lineage kinase 3 (MLK3) upregulation plays an essential role in tumor progression and correlates with an unfavorable overall survival in patients with isocitrate dehydrogenase (IDH)-wt Glioblastoma multiforme (GBM)
The present study provides evidence that MLK3 might be required for the evaluation of prognosis and targeted therapy of IDH-wt gliomas

Summary

Introduction

One of the most prevalent forms of primary brain tumors, are classified into four grades (grade I–IV) in line with the World Health Organization (WHO) 2016 classification criteria [1]. Glioblastoma multiforme (GBM) is a malignant grade IV tumor with poor prognosis. MLK3 is involved in human melanoma and breast cancers [4,5,6]. Breast tumors express a comparable level of MLK3 proteins, whereas MLK3 kinase activity is profoundly reduced and inversely correlated with tumor grades in human epidermal growth factor receptor (EGFR) 2-positive breast cancer tissues [5, 6]. In diverse human cancer cell lines, MLK3 is involved in multiple cellular processes, including proliferation, proapoptosis, migration, and invasion [4,5,6,7,8,9,10,11]. MLK3-JNK signaling has been reported to be related to EGFR activation-driven migration and invasion of GBM cell line [10]. The pathophysiological function of MLK3 in the progression and prognosis of human gliomas remains unknown, and how MLK3 promotes the development of gliomas has not been well understood

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