Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Department of Infectious Diseases, Qingdao Jimo People's Hospital, Qingdao, Shandong, China.
Cancer Med. 2023 May;12(10):11624-11640. doi: 10.1002/cam4.5859. Epub 2023 Mar 31.
Mitogen-activated protein kinase 4 (MAPK4) is an atypical member of the mitogen-activated protein kinase (MAPK) family. We report here that MAPK4 is overexpressed in glioma. The clinical significance, biological roles and underlying molecular mechanisms through which MAPK4 acts in glioma remain unclear.
Analysis of MAPK4 expression and associated survival in glioma patients was performed based on data obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases and confirmed in human glioma tissue by immunohistochemistry. MAPK4 function and pathway enrichment were analyzed through Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO). The viability and migration ability of MAPK4-silenced glioblastoma multiforme (GBM) cells were evaluated using CCK8 and transwell assays, respectively, and cell cycle and apoptosis analyses were performed using flow cytometry. Immunoblotting was used to analyze the protein level in MAPK4 knockdown glioma cells. We also analyzed the correlation of MAPK4 expression with immune infiltration and immune checkpoints in glioma.
MAPK4 was overexpressed in IDH wild-type (wt) and 1p/19q non-codeletion gliomas. MAPK4 expression predicted poor prognosis of glioma patients. MAPK4 was significantly related to functional states, including stemness, metastasis, cell cycle, differentiation and proliferation, in glioma at single-cell resolution. MAPK4 silencing inhibited proliferation and migration and induced G1 cell cycle arrest in glioma cells via the AKT/mTOR pathway. In vivo, MAPK4 knockdown markedly suppressed the growth of primary glioma. In addition, MAPK4 expression correlated negatively with the infiltration of plasmacytoid DC cells, CD8 T cells and T helper cells. Moreover, MAPK4 expression correlated positively with expression of the main immunoinhibitor checkpoint molecules and some chemokines in glioma.
MAPK4 functions as a prognostic indicator in glioma and promotes the proliferation and migration of GBM cells through the AKT/mTOR pathway. MAPK4 may participate in immune infiltration and the expression of immune checkpoints in the glioma microenvironment.
丝裂原活化蛋白激酶 4（MAPK4）是丝裂原活化蛋白激酶（MAPK）家族的一个非典型成员。我们在此报告 MAPK4 在神经胶质瘤中过度表达。MAPK4 在神经胶质瘤中的临床意义、生物学作用以及潜在的分子机制尚不清楚。
基于从癌症基因组图谱（TCGA）和中国神经胶质瘤基因组图谱（CGGA）数据库获得的数据，分析 MAPK4 表达与神经胶质瘤患者生存的相关性，并通过免疫组织化学在人神经胶质瘤组织中进行验证。通过基因集富集分析（GSEA）和基因本体论（GO）分析 MAPK4 的功能和通路富集。通过 CCK8 和 Transwell 测定分别评估 MAPK4 沉默的多形性胶质母细胞瘤（GBM）细胞的活力和迁移能力，并通过流式细胞术进行细胞周期和凋亡分析。使用免疫印迹分析 MAPK4 敲低神经胶质瘤细胞中的蛋白水平。我们还分析了 MAPK4 表达与神经胶质瘤中免疫浸润和免疫检查点的相关性。
MAPK4 在 IDH 野生型（wt）和 1p/19q 非缺失神经胶质瘤中过度表达。MAPK4 表达预测神经胶质瘤患者预后不良。MAPK4 在单细胞分辨率上与神经胶质瘤的功能状态显著相关，包括干性、转移、细胞周期、分化和增殖。MAPK4 沉默通过 AKT/mTOR 通路抑制神经胶质瘤细胞的增殖和迁移，并诱导 G1 细胞周期停滞。在体内，MAPK4 敲低显著抑制原发性神经胶质瘤的生长。此外，MAPK4 表达与浆细胞样树突状细胞、CD8 T 细胞和辅助性 T 细胞的浸润呈负相关。此外，MAPK4 表达与神经胶质瘤中主要免疫抑制剂检查点分子和一些趋化因子的表达呈正相关。
MAPK4 作为神经胶质瘤的预后指标，通过 AKT/mTOR 通路促进 GBM 细胞的增殖和迁移。MAPK4 可能参与神经胶质瘤微环境中的免疫浸润和免疫检查点的表达。
