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丝裂原活化蛋白激酶激酶激酶 1 通过 MEK/ERK 信号促进 GBM 对替莫唑胺的耐药性和迁移。

Mitogen-activated protein kinase kinase kinase 1 facilitates the temozolomide resistance and migration of GBM via the MEK/ERK signalling.

机构信息

Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, China.

出版信息

J Cell Mol Med. 2024 Oct;28(20):e70173. doi: 10.1111/jcmm.70173.

DOI:10.1111/jcmm.70173
PMID:39443331
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11499072/
Abstract

Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1) is overexpressed in gliomas; however, its clinical significance, biological functions, and underlying molecular mechanisms remain unclear. Abnormal overexpression of MAP3K1 in glioma is strongly associated with unfavourable clinicopathological characteristics and disease progression. MAP3K1 could potentially serve as a reliable diagnostic and prognostic biomarker for glioma. MAP3K1 silencing suppressed the migration but had no effect on the proliferation and cell death of Glioblastoma Multiforme (GBM) cells. MAP3K1 knockdown exacerbated the temozolomide (TMZ) induced inhibition of glioma cell proliferation and death of GBM cells. In addition, MAP3K1 knockdown combined with TMZ treatment significantly inhibited the growth and increased cell death in organoids derived from GBM patients. MAP3K1 knockdown reversed TMZ resistance of GBM in intracranial glioma model. In terms of molecular mechanisms, the phosphorylation level of ERK was significantly decreased by MAP3K1 silencing. No significant change in the JNK pathway was found in MAP3K1-silenced GBM cells. Inhibition of ERK phosphorylation suppressed the migration and enhanced the TMZ sensibility of GBM cells. MAP3K1 was correlated with the immune infiltration in glioma. MAP3K1 could facilitate the migration and TMZ resistance of GBM cells through MEK/ERK signalling.

摘要

丝裂原活化蛋白激酶激酶激酶 1（MAP3K1）在神经胶质瘤中过表达；然而，其临床意义、生物学功能和潜在的分子机制尚不清楚。MAP3K1 在神经胶质瘤中的异常过表达与不良的临床病理特征和疾病进展密切相关。MAP3K1 可能作为神经胶质瘤可靠的诊断和预后生物标志物。MAP3K1 沉默抑制了胶质母细胞瘤（GBM）细胞的迁移，但对增殖和细胞死亡没有影响。MAP3K1 敲低加剧了替莫唑胺（TMZ）诱导的对胶质瘤细胞增殖的抑制和 GBM 细胞的死亡。此外，MAP3K1 敲低联合 TMZ 治疗显著抑制了源自 GBM 患者的类器官的生长并增加了细胞死亡。MAP3K1 敲低逆转了颅内神经胶质瘤模型中 GBM 的 TMZ 耐药性。在分子机制方面，MAP3K1 沉默显著降低了 ERK 的磷酸化水平。在 MAP3K1 沉默的 GBM 细胞中未发现 JNK 途径有明显变化。抑制 ERK 磷酸化抑制了 GBM 细胞的迁移并增强了 TMZ 的敏感性。MAP3K1 与胶质瘤中的免疫浸润相关。MAP3K1 可通过 MEK/ERK 信号通路促进 GBM 细胞的迁移和 TMZ 耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/03e7319561e7/JCMM-28-e70173-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/49f60ea9db69/JCMM-28-e70173-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/4a5c8901ec47/JCMM-28-e70173-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/219aae1de781/JCMM-28-e70173-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/b64eeda071b1/JCMM-28-e70173-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/baac145f3ba5/JCMM-28-e70173-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/03e7319561e7/JCMM-28-e70173-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/49f60ea9db69/JCMM-28-e70173-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/4a5c8901ec47/JCMM-28-e70173-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/219aae1de781/JCMM-28-e70173-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/b64eeda071b1/JCMM-28-e70173-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/baac145f3ba5/JCMM-28-e70173-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86dd/11499072/03e7319561e7/JCMM-28-e70173-g004.jpg

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本文引用的文献

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Author Correction: EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood.作者更正：欧洲神经肿瘤协会（EANO）成人弥漫性胶质瘤诊断和治疗指南。
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The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.2021 年世卫组织中枢神经系统肿瘤分类：概述。
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Curr Neuropharmacol. 2021;19(4):513-537. doi: 10.2174/1570159X18666200626204005.
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Map3k1 Loss Cooperates with Braf to Drive Melanomagenesis.Map3k1缺失与Braf协同作用驱动黑色素瘤发生。
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miRNA-627 inhibits cell proliferation and cell migration, promotes cell apoptosis in prostate cancer cells through upregulating MAP3K1, PTPRK and SRA1.微小RNA-627通过上调丝裂原活化蛋白激酶激酶激酶1（MAP3K1）、蛋白酪氨酸磷酸酶受体K（PTPRK）和类固醇受体RNA激活因子1（SRA1）来抑制前列腺癌细胞的增殖和迁移，并促进其凋亡。
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7
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