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Nucleic Acids Res. 2019 Apr 23;47(7):3365-3382. doi: 10.1093/nar/gkz041.

TRF2 positively regulates SULF2 expression increasing VEGF-A release and activity in tumor microenvironment.

Author information

1
Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
2
SAFU, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
3
Pathology, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
4
Department of Biostatistics Unit, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
5
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Università della Campania Luigi Vanvitelli, via Vivaldi 43, 80100 Caserta.
6
Cancer Genomics Lab, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900 Biella.
7
Université Côte d'Azur, CNRS UMR 7284/INSERM U108, Institute for Research on Cancer and Aging, Nice (IRCAN), Medical School, Nice, France.
8
Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, France.

Abstract

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.

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