Zhu Yan, Sun Jin-Min, Sun Zi-Chen, Chen Feng-Jiao, Wu Yong-Ping, Hou Xiao-Yu
Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, China.
State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
Front Oncol. 2021 Feb 22;10:600762. doi: 10.3389/fonc.2020.600762. eCollection 2020.
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 ()-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 -wt gliomas and suggest that MLK3 promotes the migration and invasion of GBM cells by remodeling the actin cytoskeleton MLK3-EPS8 signaling.
混合谱系激酶3（MLK3）与人类黑色素瘤和乳腺癌有关。然而，MLK3在人类胶质瘤中的临床意义以及潜在的细胞和分子机制仍不清楚。我们发现，MLK3蛋白在高级别人类胶质瘤标本中高表达，尤其在原发性和复发性多形性胶质母细胞瘤（GBM）中普遍存在。MLK3 mRNA的高水平与异柠檬酸脱氢酶（）野生型（wt）胶质瘤患者的不良预后相关。此外，MLK3的基因消融显著抑制了GBM细胞的迁移和侵袭能力，并破坏了肌动蛋白细胞骨架组织。重要的是，MLK3直接与表皮生长因子受体激酶底物8（EPS8）结合，并调节EPS8的细胞定位，这对肌动蛋白细胞骨架重排至关重要。总体而言，这些发现提供了证据，表明MLK3上调预示着人类-wt胶质瘤的进展和不良预后，并表明MLK3通过重塑肌动蛋白细胞骨架MLK3-EPS8信号促进GBM细胞的迁移和侵袭。
