TY - JOUR
T1 - GFAPδ/GFAPα ratio directs astrocytoma gene expression towards a more malignant profile
AU - Stassen, Oscar M J A
AU - van Bodegraven, Emma J.
AU - Giuliani, Fabrizio
AU - Moeton, Martina
AU - Kanski, Regina
AU - Sluijs, Jacqueline A.
AU - van Strien, Miriam E.
AU - Kamphuis, Willem
AU - Robe, Pierre A.J.
AU - Hol, Elly M.
N1 - Funding Information:
GFAPδ/α ratio controls astrocytoma malignancy by regulating tumour growth. This is supported by the increase in cell proliferation induced by the increased GFAPδ/α ratio in astrocytoma (Figure 3D-3E). Previous studies indeed report a functional role of our identified GFAP-regulated gene set in the regulation of proliferation, mitosis, and tumour growth. While the high-malignant gene SPC24 positively regulates cell proliferation [40, 49], the low-malignant gene FBXO2 induces growth arrest [50, 51]. NOS2 and VAV3 stimulate glioma-initiating cell proliferation and tumour growth in xenograft models [34, 52].
Publisher Copyright:
© Stassen et al.
PY - 2017
Y1 - 2017
N2 - Astrocytomas are the most common malignant brain tumours and are to date incurable. It is unclear how astrocytomas progress into higher malignant grades. The intermediate filament cytoskeleton is emerging as an important regulator of malignancy in several tumours. The majority of the astrocytomas express the intermediate filament protein Glial Fibrillary Acidic Protein (GFAP). Several GFAP splice variants have been identified and the main variants expressed in human astrocytoma are the GFAPα and GFAPδ isoforms. Here we show a significant downregulation of GFAPα in grade IV astrocytoma compared to grade II and III, resulting in an increased GFAPδ/α ratio. Mimicking this increase in GFAPδ/α ratio in astrocytoma cell lines and comparing the subsequent transcriptomic changes with the changes in the patient tumours, we have identified a set of GFAPδ/α ratio-regulated high-malignant and low-malignant genes. These genes are involved in cell proliferation and protein phosphorylation, and their expression correlated with patient survival. We additionally show that changing the ratio of GFAPδ/α, by targeting GFAP expression, affected expression of high-malignant genes. Our data imply that regulating GFAP expression and splicing are novel therapeutic targets that need to be considered as a treatment for astrocytoma.
AB - Astrocytomas are the most common malignant brain tumours and are to date incurable. It is unclear how astrocytomas progress into higher malignant grades. The intermediate filament cytoskeleton is emerging as an important regulator of malignancy in several tumours. The majority of the astrocytomas express the intermediate filament protein Glial Fibrillary Acidic Protein (GFAP). Several GFAP splice variants have been identified and the main variants expressed in human astrocytoma are the GFAPα and GFAPδ isoforms. Here we show a significant downregulation of GFAPα in grade IV astrocytoma compared to grade II and III, resulting in an increased GFAPδ/α ratio. Mimicking this increase in GFAPδ/α ratio in astrocytoma cell lines and comparing the subsequent transcriptomic changes with the changes in the patient tumours, we have identified a set of GFAPδ/α ratio-regulated high-malignant and low-malignant genes. These genes are involved in cell proliferation and protein phosphorylation, and their expression correlated with patient survival. We additionally show that changing the ratio of GFAPδ/α, by targeting GFAP expression, affected expression of high-malignant genes. Our data imply that regulating GFAP expression and splicing are novel therapeutic targets that need to be considered as a treatment for astrocytoma.
KW - GFAP-isoforms
KW - astrocytoma
KW - transcriptomics
KW - glioma
KW - intermediate filaments
UR - http://www.scopus.com/inward/record.url?scp=85031730235&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.21540
DO - 10.18632/oncotarget.21540
M3 - Article
AN - SCOPUS:85031730235
SN - 1949-2553
VL - 8
SP - 88104
EP - 88121
JO - Oncotarget
JF - Oncotarget
IS - 50
ER -