Elsevier

Neoplasia

Volume 11, Issue 9, September 2009, Pages 921-933, IN6-IN7
Neoplasia

Transcriptional Regulation of Vascular Endothelial Growth Factor C by Oxidative and Thermal Stress Is Mediated by Lens Epithelium-Derived Growth Factor/p751,2

https://doi.org/10.1593/neo.09636Get rights and content
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open access

Abstract

Vascular endothelial growth factor C (VEGF-C) plays a critical role in tumor lymphangiogenesis and lymph node metastasis. We report here that VEGF-C expression is regulated by microenvironmental stress including hyperthermia and oxidative stress. Furthermore, we show that this stress response is mediated by transcriptional activation mediated by lens epithelium-derived growth factor (LEDGF/p75). Ectopic expression of LEDGF/p75 in C6 rat glioma and in H1299 human non-small cell lung carcinoma induced VEGF-C expression in vitro, whereas in subcutaneous mouse tumor xenografts, LEDGF/p75 stimulated VEGF-C expression and augmented angiogenesis and lymphangiogenesis. Conversely, overexpression of a LEDGF/p75 native antisense or LEDGF/p75-targeted short interfering RNA downmodulated VEGF-C expression. LEDGF seemed to conferred this activity on binding to a conserved stress response element (STRE) located in the VEGF-C gene because mutating the STRE was sufficient for the suppression of basal and stress-induced activations of the VEGF-C promoter. Thus, the study reported here identified a role for LEDGF/p75 in stress-regulated transcriptional control of VEGF-C expression. These results provide a possible link for LEDGF/p75 in tumor lymphangiogenesis and cancer metastasis. Hence, our data suggest the LEDGF-VEGF-C axis as a putative biomarker for the detection of stress-induced lymphangiogenesis and LEDGF as a potential target for antimetastatic therapy.

Abbreviations

DLSI
dynamic light scattering imaging
LEDGF
lens epithelium-derived growth factor
STRE
stress response element
VEGF
vascular endothelial growth factor

Cited by (0)

1

This work was supported by the Israel Science Foundation 93/07 (to M.N. and B.C.) and by National Institutes of Health grant R01 CA75334 and the 7th Framework European Research Council Advanced grant 232640-IMAGO (to M.N.). M.N. is incumbent of the Helen and Morris Mauerberger Chair.

2

This article refers to supplementary materials, which are designated by Figures W1 to W4 and are available online at www.neoplasia.com.

3

These authors contributed equally to this work.