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GAS5 attenuates the malignant progression of glioma stem-like cells by promoting E-cadherin

Cancer Gene Therapy volume 30, pages 450–461 (2023)Cite this article

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Abstract

It has been widely reported that glioma stem-like cells (GSCs) serve a crucial role in the malignant progression of glioma. In particular, recent studies have reported that long non-coding RNAs (lncRNAs) are closely associated with glioma development. However, the underlying molecular regulatory mechanistic role of GSCs remains poorly understood. The present study established two highly malignant glioma stem-like cell lines from clinical surgical specimens. In these, it was found that the lncRNA growth arrest-specific 5 (GAS5) expression was downregulated in GSCs and high-grade glioma tissues, compared with normal human astrocyte cells (NHAs) and normal brain tissues, respectively, which also showed a positive correlation with patient survival. Functional assays revealed that knocking down GAS5 expression promoted the proliferation, invasion, migration, stemness, and tumorigenicity of GSGs, while suppressing their apoptosis. Mechanistically, GAS5 directly sponged miR-23a, which in turn functioned as an oncogene by inhibiting E-cadherin, through the assays of reverse transcription-quantitative PCR (RT-qPCR) and luciferase reports. In addition, rescue experiments demonstrated that GAS5 could promote the expression and function of E-cadherin in a miR-23a-dependent manner. Collectively, these data suggest that GAS5 functions as a suppressor in GSCs by targeting the miR-23a/E-cadherin axis, which may be a promising therapeutic target against glioma.

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Fig. 1: Expression of GAS5 is negatively associated with the malignancy of glioma.
Fig. 2: Primary culture of GSCs derived from clinical specimens.
Fig. 3: GAS5 overexpression inhibits the proliferation, invasion, migration, and stemness of GSCs while promoting apoptosis in vitro.
Fig. 4: Silencing GAS5 promotes proliferation, invasion, migration, and stemness while inhibiting apoptosis in GSCs in vitro.
Fig. 5: GAS5 overexpression inhibits the growth of GSCs in vivo.
Fig. 6: GAS5 functions as a sponge for miR-23a in GSCs.
Fig. 7: miR-23a knockdown inhibits the proliferation, invasion, and migration of GSCs while promoting apoptosis by targeting CDH1.
Fig. 8: Knocking down GAS5 promotes the proliferation, invasion, and migration of GSCs while inhibiting apoptosis by targeting miR-23a.

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All raw data of the study was available.

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Acknowledgements

This study was supported by grants from the agricultural and social development project of Hangzhou (grant no. 20211231Y025; grant no. 202204B11).

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  1. These authors contributed equally: Haiyang Wang, Ding Wang.

Authors and Affiliations

  1. Department of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, P.R. China

    Haiyang Wang, Ding Wang, Yongfeng Shen, Chenglong Sun, Qiang Hu, Li Jiang & Quan Du

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Contributions

QD is responsible for the design of the study; HW is responsible for experimental implementation; DW is responsible for collection and analysis of data; YS and CS are responsible for the writing the manuscript; QH and LJ are responsible for reviewing the manuscript. All authors have read and approved the manuscript.

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Correspondence to Quan Du.

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Wang, H., Wang, D., Shen, Y. et al. GAS5 attenuates the malignant progression of glioma stem-like cells by promoting E-cadherin. Cancer Gene Ther 30, 450–461 (2023). https://doi.org/10.1038/s41417-022-00566-y

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