GFAPδ/GFAPα ratio directs astrocytoma gene expression towards a more malignant profile

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)


Interna författare/redaktörer


Publikationens författare: Stassen OMJA, van Bodegraven EJ, Giuliani F, Moeton M, Kanski R, Sluijs JA, van Strien ME, Kamphuis W, Robe PAJ, Hol EM
Förläggare: IMPACT JOURNALS LLC
Publiceringsår: 2017
Tidskrift: Oncotarget
Tidskriftsakronym: ONCOTARGET
Volym: 8
Nummer: 50
Artikelns första sida, sidnummer: 88104
Artikelns sista sida, sidnummer: 88121
Antal sidor: 18
ISSN: 1949-2553


Abstrakt

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 GFAP alpha and GFAP delta isoforms. Here we show a significant downregulation of GFAP alpha in grade IV astrocytoma compared to grade II and III, resulting in an increased GFAP delta/alpha ratio. Mimicking this increase in GFAP delta/alpha ratio in astrocytoma cell lines and comparing the subsequent transcriptomic changes with the changes in the patient tumours, we have identified a set of GFAP delta/alpha 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 GFAP delta/alpha, 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.


Nyckelord

astrocytoma, GFAP-isoforms, glioma, intermediate filaments

Senast uppdaterad 2020-21-01 vid 03:34