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Transcription factors NFIA and NFIB induce cellular differentiation in high-grade astrocytoma

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Abstract

Introduction

Malignant astrocytomas are composed of heterogeneous cell populations. Compared to grade IV glioblastoma, low-grade astrocytomas have more differentiated cells and are associated with a better prognosis. Therefore, inducing cellular differentiation to alter the behaviour of high-grade astrocytomas may serve as a therapeutic strategy. The nuclear factor one (NFI) transcription factors are essential for normal astrocytic differentiation. Here, we investigate whether family members NFIA and NFIB act as effectors of cellular differentiation in glioblastoma.

Methods

We analysed expression of NFIA and NFIB in mRNA expression data of high-grade astrocytoma and with immunofluorescence co-staining. Furthermore, we induced NFI expression in patient-derived subcutaneous glioblastoma xenografts via in vivo electroporation.

Results

The expression of NFIA and NFIB is reduced in glioblastoma as compared to lower grade astrocytomas. At a cellular level, their expression is associated with differentiated and mature astrocyte-like tumour cells. In vivo analyses consistently demonstrate that expression of either NFIA or NFIB is sufficient to promote tumour cell differentiation in glioblastoma xenografts.

Conclusion

Our findings indicate that both NFIA and NFIB may have an endogenous pro-differentiative function in astrocytomas, similar to their role in normal astrocyte differentiation. Overall, our study establishes a basis for further investigation of targeting NFI-mediated differentiation as a potential differentiation therapy.

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Acknowledgements

We thank the staff of the University of Queensland Biological Resources (UQBR) animal facility and the QBI Advanced Microscopy and Analysis Facility for their expertise and assistance in this project. We thank Rowan Tweedale for critical comments on the manuscript and Alan Ho for expert assistance with statistical analyses. We thank Andrew W. Boyd and Richard M. Gronostajski for their advice on this project. The primary human GBM samples and de-identified data used in this project were sourced from the Wesley Medical Research Tissue Bank with appropriate ethics approval.

Funding

This work was supported by the National Health and Medical Research Council (NHMRC) [GNT1100443, GNT1120615 to LJR]; Tour de Cure [Young Research Grant to JB]; Brain Foundation [research gift to JB]; Ride for Rhonda [research gift to LJR and JB to support CRB]; the University of Malaya [RP049-17HTM to HA]; the University of Queensland (UQ) [International Postgraduate Student Scholarship to KSC, UQ Graduate School Scholarship to ZL, UQ Centennial Scholarship to JWCL]; the Australian Government [Research Training Program Scholarship to JWCL].

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  1. Linda J. Richards and Jens Bunt have contributed equally to this manuscript.

Authors and Affiliations

  1. The Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia

    Kok-Siong Chen, Caitlin R. Bridges, Zorana Lynton, Jonathan W. C. Lim, Linda J. Richards & Jens Bunt

  2. The Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia

    Zorana Lynton

  3. QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia

    Brett W. Stringer & Bryan W. Day

  4. Department of Paediatrics, University of Malaya, 59100, Kuala Lumpur, Malaysia

    Revathi Rajagopal & Hany Ariffin

  5. Department of Pathology, University of Malaya, 59100, Kuala Lumpur, Malaysia

    Kum-Thong Wong

  6. Division of Neurosurgery, University of Malaya Medical Centre, 59100, Kuala Lumpur, Malaysia

    Dharmendra Ganesan

  7. School of Biomedical Sciences, The Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia

    Linda J. Richards

  8. Queensland Brain Institute, The University of Queensland, Building 79, Upland Rd Brisbane, Brisbane, QLD, 4072, Australia

    Linda J. Richards & Jens Bunt

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Contributions

Study concept and design: KSC, LJR, JB. Acquisition of data: KSC, CRB, ZL, JB. Analysis and interpretation of data: KSC, CRB, ZL, JWCL, LJR, JB. GBM cell lines: BWS, BWD. Pathology: RR, KTW, DG, HA. Drafting of the manuscript: KSC, JB, LJR. Revision of the manuscript: KSC, JWCL, ZL, BWS, RR, KTW, DG, HA, BWD, LJR, JB. Administrative and technical support: CRB. Obtained funding: LJR, JB. Study supervision: LJR, JB.

Corresponding authors

Correspondence to Linda J. Richards or Jens Bunt.

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The authors declare no conflict of interest.

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All procedures performed in studies involving human material were in accordance with the ethical standards of the institutional research committee (University of Queensland Human Ethics Committee) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All procedures performed in studies involving animals were in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, and with the approval of the University of Queensland Animal Ethics Committee.

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Chen, KS., Bridges, C.R., Lynton, Z. et al. Transcription factors NFIA and NFIB induce cellular differentiation in high-grade astrocytoma. J Neurooncol 146, 41–53 (2020). https://doi.org/10.1007/s11060-019-03352-3

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