Department of Neurosurgery, Yuquan Hospital, Tsinghua University, No. 5 Shijingshan Road, Shijingshan District, Beijing, 100040, People's Republic of China.
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People's Republic of China.
J Cancer Res Clin Oncol. 2018 Dec;144(12):2351-2366. doi: 10.1007/s00432-018-2745-y. Epub 2018 Sep 17.
MicroRNAs (miRs) play an important role in many cancers and can affect cancer cell behavior, including glioma. This study aims at investigating the effects of miR-338-5p on the senescence, migration, invasion, and apoptosis of glioma cells via MAPK-signaling pathway by binding to FOXD1.
Gene expression microarray analysis was performed to screen differentially expressed miRNAs associated with glioma. Glioma tissues and adjacent tissues were collected. siRNA, mimic, and inhibitor were introduced for investigating the tumor suppressor role of miR-338-5p in glioma. Proliferation, migration, invasion, senescence, cell-cycle distribution, and apoptosis after transfection were detected by MTT assay, scratch test, Transwell assay, β-galactosidase staining, and flow cytometry, respectively.
FOXD1 was identified as the up-regulated gene in glioma based on microarray data of GSE65626. FOXD1 was the target gene of miR-338-5p. Glioma tissues had increased expression of FOXD1, MEK-2, ERK-1, DAF, PCNA, and Bcl-2, and decreased expression of miR-338-5p and Bax. In cell experiments, after transfected with overexpressed miR-338-5p, higher expression of miR-338-5p, Bax, CD133, ZEB1, SOX2, SNAI1, and MMP2, but lower expression of FOXD1, MEK-2, ERK-1, Bcl-2, DAF, and PCNA were found accompanied with weaker proliferation, migration and invasion as well as stemness abilities but stronger senescence and higher apoptosis rate.
We found that overexpression of miR-338-5p suppresses glioma cell proliferation, migration, and invasion and accelerates its senescence and apoptosis by decreasing FOXD1 expression via inhibition of activation of MAPK-signaling pathway.
MicroRNAs（miRs）在许多癌症中发挥重要作用，可影响包括神经胶质瘤在内的癌细胞行为。本研究旨在通过结合 FOXD1 研究 miR-338-5p 通过 MAPK 信号通路对神经胶质瘤细胞衰老、迁移、侵袭和凋亡的影响。
采用基因表达微阵列分析筛选与神经胶质瘤相关的差异表达 miRNA。收集神经胶质瘤组织和相邻组织。通过转染检测 miR-338-5p 在神经胶质瘤中的肿瘤抑制作用，引入 siRNA、mimic 和抑制剂。MTT 检测、划痕试验、Transwell 试验、β-半乳糖苷酶染色和流式细胞术分别检测转染后细胞增殖、迁移、侵袭、衰老、细胞周期分布和凋亡。
基于 GSE65626 的基因芯片数据，确定 FOXD1 为神经胶质瘤上调基因。FOXD1 是 miR-338-5p 的靶基因。神经胶质瘤组织中 FOXD1、MEK-2、ERK-1、DAF、PCNA 和 Bcl-2 表达增加，miR-338-5p 和 Bax 表达减少。在细胞实验中，转染过表达 miR-338-5p 后，miR-338-5p、Bax、CD133、ZEB1、SOX2、SNAI1 和 MMP2 表达上调，FOXD1、MEK-2、ERK-1、Bcl-2、DAF 和 PCNA 表达下调，细胞增殖、迁移和侵袭能力减弱，衰老和凋亡率增加。
我们发现，过表达 miR-338-5p 通过抑制 MAPK 信号通路的激活，降低 FOXD1 表达，抑制神经胶质瘤细胞增殖、迁移和侵袭，促进其衰老和凋亡。
