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Forkhead box protein D1 (Forkhead-related protein FKHL8) (Forkhead-related transcription factor 4) (FREAC-4) [FKHL8] [FREAC4]


MicroRNA-338-5p plays a tumor suppressor role in glioma through inhibition of the MAPK-signaling pathway by binding to FOXD1.

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.

MeSH Terms

  • Apoptosis
  • Biomarkers
  • Brain Neoplasms
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Computational Biology
  • Forkhead Transcription Factors
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter
  • Genes, Tumor Suppressor
  • Glioma
  • Humans
  • MicroRNAs
  • Mitogen-Activated Protein Kinases
  • Neoplastic Stem Cells
  • RNA Interference
  • Signal Transduction


  • FOXD1
  • Glioma cells
  • Invasion
  • MAPK-signaling pathway
  • MicroRNA-338-5p
  • Migration
  • Proliferation
  • Senescence