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Cytoplasmic cyclin D1 regulates glioblastoma dissemination.
- Source :
-
The Journal of pathology [J Pathol] 2019 Aug; Vol. 248 (4), pp. 501-513. Date of Electronic Publication: 2019 May 16. - Publication Year :
- 2019
-
Abstract
- Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The cyclin D1 (Ccnd1)/Cdk4-retinoblastoma 1 (RB1) axis is frequently altered in GBM, leading to overproliferation by RB1 deletion or by Ccnd1-Cdk4 overactivation. High levels of Ccnd1-Cdk4 also promote GBM cell invasion by mechanisms that are not so well understood. The purpose of this work is to elucidate the in vivo role of cytoplasmic Ccnd1-Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates the invasion of primary human GBM cells through cytoplasmic RB1-independent mechanisms. By using GBM mouse models, we observed that evaded GBM cells showed cytoplasmic Ccnd1 colocalizing with regulators of cell invasion such as RalA and paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1-Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces focal adhesion kinase, RalA and Rac1 activities. Finally, in vivo experiments demonstrated increased GBM dissemination after expression of membrane-targeted Ccnd1. We conclude that Ccnd1-Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1-independent mechanisms. Therefore, inhibition of Ccnd1-Cdk4 activity may be useful to hinder the dissemination of recurrent GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.<br /> (© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Subjects :
- Animals
Biomarkers, Tumor metabolism
Brain Neoplasms metabolism
Brain Neoplasms pathology
Cell Line, Tumor
Cell Movement
Cyclin D1 metabolism
Cytoplasm metabolism
Glioblastoma metabolism
Glioblastoma pathology
Humans
Male
Mice
Mice, SCID
Neoplasm Invasiveness
Biomarkers, Tumor genetics
Brain Neoplasms genetics
Cyclin D1 genetics
Gene Expression Regulation, Neoplastic
Glioblastoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1096-9896
- Volume :
- 248
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 30957234
- Full Text :
- https://doi.org/10.1002/path.5277