TRF2 positively regulates SULF2 expression increasing VEGF-A release and activity in tumor microenvironment.
Animals
Cell Line, Tumor
Colonic Neoplasms
/ blood supply
Heparan Sulfate Proteoglycans
/ chemistry
Heparin
/ metabolism
Humans
Male
Mice
Mice, Nude
Neoplasm Metastasis
Neovascularization, Pathologic
Sulfatases
Sulfotransferases
/ biosynthesis
Telomeric Repeat Binding Protein 2
/ deficiency
Tumor Microenvironment
Vascular Endothelial Growth Factor A
/ metabolism
Xenograft Model Antitumor Assays
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
23 04 2019
23 04 2019
Historique:
accepted:
16
01
2019
received:
20
12
2018
pubmed:
31
1
2019
medline:
29
10
2019
entrez:
31
1
2019
Statut:
ppublish
Résumé
The telomeric protein TRF2 is overexpressed in several human malignancies and contributes to tumorigenesis even though the molecular mechanism is not completely understood. By using a high-throughput approach based on the multiplexed Luminex X-MAP technology, we demonstrated that TRF2 dramatically affects VEGF-A level in the secretome of cancer cells, promoting endothelial cell-differentiation and angiogenesis. The pro-angiogenic effect of TRF2 is independent from its role in telomere capping. Instead, TRF2 binding to a distal regulatory element promotes the expression of SULF2, an endoglucosamine-6-sulfatase that impairs the VEGF-A association to the plasma membrane by inducing post-synthetic modification of heparan sulfate proteoglycans (HSPGs). Finally, we addressed the clinical relevance of our findings showing that TRF2/SULF2 expression is a worse prognostic biomarker in colorectal cancer (CRC) patients.
Identifiants
pubmed: 30698737
pii: 5304306
doi: 10.1093/nar/gkz041
pmc: PMC6468246
doi:
Substances chimiques
Heparan Sulfate Proteoglycans
0
TERF2 protein, human
0
Telomeric Repeat Binding Protein 2
0
VEGFA protein, human
0
Vascular Endothelial Growth Factor A
0
Heparin
9005-49-6
Sulfotransferases
EC 2.8.2.-
SULF2 protein, human
EC 3.1.6.-
Sulfatases
EC 3.1.6.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3365-3382Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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