Kok-Siong Chen1, Caitlin R Bridges1, Zorana Lynton1,2, Jonathan W C Lim1, Brett W Stringer3, Revathi Rajagopal4, Kum-Thong Wong5, Dharmendra Ganesan6, Hany Ariffin4, Bryan W Day3, Linda J Richards7,8,9, Jens Bunt10,11. 1. The Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia. 2. The Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia. 3. QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. 4. Department of Paediatrics, University of Malaya, 59100, Kuala Lumpur, Malaysia. 5. Department of Pathology, University of Malaya, 59100, Kuala Lumpur, Malaysia. 6. Division of Neurosurgery, University of Malaya Medical Centre, 59100, Kuala Lumpur, Malaysia. 7. The Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia. richards@uq.edu.au. 8. School of Biomedical Sciences, The Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia. richards@uq.edu.au. 9. Queensland Brain Institute, The University of Queensland, Building 79, Upland Rd Brisbane, Brisbane, QLD, 4072, Australia. richards@uq.edu.au. 10. The Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia. j.bunt@uq.edu.au. 11. Queensland Brain Institute, The University of Queensland, Building 79, Upland Rd Brisbane, Brisbane, QLD, 4072, Australia. j.bunt@uq.edu.au.
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.
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.
Entities:
Keywords:
Astrocytoma; Differentiation; Glioblastoma; NFIA; NFIB; Nuclear factor I
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