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

Jung-Jyh Hung,Chi-Hung Huang,Wen-Hu Hsu,Ying-Shiun Kao

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.

Highlights

Aiolos/Ikaros family zinc finger 3 (IKZF3), a member of the Ikaros family of lymphocyte maturationdriving transcription factors, is highly expressed in hematopoietic malignancies
The decreased E-cadherin and increased vimentin expressions were confirmed by qRT-polymerase chain reaction (PCR) in H1299-Aiolos (Supplementary Fig. 2B,C) and A549-Aiolos cells (Supplementary Fig. 3B,C)
The expression of matrix metalloproteinase 16 (MMP16) was upregulated in H1299-Aiolos and A549-Aiolos cells (Fig. 3A). All these results showed that Aiolos overexpression upregulates the Twist/MMP16 expression, and leads to induction of epithelial-mesenchymal transition (EMT) in lung cancer cells

Summary

Introduction

Aiolos/Ikaros family zinc finger 3 (IKZF3), a member of the Ikaros family of lymphocyte maturationdriving transcription factors, is highly expressed in hematopoietic malignancies. Its role in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like properties in lung cancer remains unknown. 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 reversed by an inhibitor of PI 3-kinase. Aiolos overexpression promotes EMT and CSC-like properties through upregulating the PI 3-kinase/Akt pathway. IKZF1 promotes metastatic ability through upregulating Slug and matrix metalloproteinase 2 (MMP2) in ovarian cancer[30]. Whether Aiolos expression promotes EMT and CSC-like properties in lung cancer remains unknown. Since the relationship between Aiolos expression and EMT or CSC-like properties in lung cancer cells has not been well demonstrated, the current study aims to demonstrate the regulating mechanisms Aiolos expression promoting EMT and CSC-like properties in lung cancer cells

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Results

Conclusion