WIF1 re-expression in glioblastoma inhibits migration through attenuation of non-canonical WNT signaling by downregulating the lncRNA MALAT1.

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Version: Author's accepted manuscript
Serval ID
serval:BIB_40732EBE5882
Type
Article: article from journal or magazin.
Collection
Publications
Title
WIF1 re-expression in glioblastoma inhibits migration through attenuation of non-canonical WNT signaling by downregulating the lncRNA MALAT1.
Journal
Oncogene
Author(s)
Vassallo I., Zinn P., Lai M., Rajakannu P., Hamou M.F., Hegi M.E.
ISSN
1476-5594 (Electronic)
ISSN-L
0950-9232
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
35
Number
1
Pages
12-21
Language
english
Abstract
Glioblastoma is the most aggressive primary brain tumor in adults and due to the invasive nature cannot be completely removed. The WNT inhibitory factor 1 (WIF1), a secreted inhibitor of WNTs, is systematically downregulated in glioblastoma and acts as strong tumor suppressor. The aim of this study was the dissection of WIF1-associated tumor-suppressing effects mediated by canonical and non-canonical WNT signaling. We found that WIF1 besides inhibiting the canonical WNT pathway selectively downregulates the WNT/calcium pathway associated with significant reduction of p38-MAPK (p38-mitogen-activated protein kinase) phosphorylation. Knockdown of WNT5A, the only WNT ligand overexpressed in glioblastoma, phenocopied this inhibitory effect. WIF1 expression inhibited cell migration in vitro and in an orthotopic brain tumor model, in accordance with the known regulatory function of the WNT/Ca(2+) pathway on migration and invasion. In search of a mediator for this function differential gene expression profiles of WIF1-expressing cells were performed. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA and key positive regulator of invasion, emerged as the top downregulated gene. Indeed, knockdown of MALAT1 reduced migration in glioblastoma cells, without effect on proliferation. Hence, loss of WIF1 enhances the migratory potential of glioblastoma through WNT5A that activates the WNT/Ca(2+) pathway and MALAT1. These data suggest the involvement of canonical and non-canonical WNT pathways in glioblastoma promoting key features associated with this deadly disease, proliferation on one hand and invasion on the other. Successful targeting will require a dual strategy affecting both canonical and non-canonical WNT pathways.
Keywords
Adaptor Proteins, Signal Transducing/biosynthesis, Adaptor Proteins, Signal Transducing/genetics, Animals, Brain Neoplasms/genetics, Brain Neoplasms/metabolism, Cell Line, Tumor, Cell Movement/physiology, Cell Proliferation/physiology, Down-Regulation, Gene Expression Regulation, Neoplastic, Glioblastoma/genetics, Glioblastoma/metabolism, Heterografts, Humans, Mice, Mice, Nude, Proto-Oncogene Proteins/genetics, Proto-Oncogene Proteins/metabolism, RNA, Long Noncoding/genetics, RNA, Long Noncoding/metabolism, Repressor Proteins/biosynthesis, Repressor Proteins/genetics, Signal Transduction, Wnt Proteins/genetics, Wnt Proteins/metabolism, Wnt Signaling Pathway
Pubmed
Web of science
Open Access
Yes
Create date
02/02/2016 18:17
Last modification date
20/08/2019 14:38
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