Overexpression of Aiolos promotes epithelial-mesenchymal transition and cancer stem cell-like properties in lung cancer cells

Sci Rep. 2019 Feb 28;9(1):2991. doi: 10.1038/s41598-019-39545-z.

Abstract

Aiolos/Ikaros family zinc finger 3 (IKZF3), a member of the Ikaros family of lymphocyte maturation-driving transcription factors, is highly expressed in hematopoietic malignancies. However, its role in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like properties in lung cancer remains unknown. Human lung cancer cell lines H1299 with overexpressing Aiolos (H1299-Aiolos) and A549 with overexpressing Aiolos (A549-Aiolos) were generated by stable transfection. Cell migration and invasion assays were done to demonstrate their invasion and migration ability. Sphere formation assay was used to determine their tumor-initiating capability. Aiolos overexpression induced EMT and increased migration/invasiveness in H1299 and A549 cells. Aiolos overexpression also increased metastatic ability in vivo. Aiolos overexpression upregulated the expression of Twist and matrix metalloproteinase 16 (MMP16). By using knockdown of Twist or an inhibitor of phosphatidylinositol (PI) 3-kinase, EMT, migration/invasiveness ability, and MMP16 expression were reversed in H1299-Aiolos and A549-Aiolos cells. Overexpression of Aiolos upregulated the CSC-like properties in lung cancer cells, and were also reversed by an inhibitor of PI 3-kinase. For lung cancer cells, Aiolos overexpression promotes EMT and CSC-like properties through upregulating the PI 3-kinase/Akt pathway. The information is helpful for developing therapeutic strategies targeting Aiolos expression for lung cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Movement
  • Epithelial-Mesenchymal Transition*
  • Humans
  • Ikaros Transcription Factor / genetics*
  • Ikaros Transcription Factor / metabolism
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Matrix Metalloproteinase 16 / genetics
  • Matrix Metalloproteinase 16 / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplastic Stem Cells / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism
  • Up-Regulation

Substances

  • IKZF3 protein, human
  • MMP16 protein, human
  • Nuclear Proteins
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • Ikaros Transcription Factor
  • Matrix Metalloproteinase 16