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Transcriptional regulation of vascular endothelial growth factor C by oxidative and thermal stress is mediated by lens epithelium-derived growth factor/p75.
- Source :
-
Neoplasia (New York, N.Y.) [Neoplasia] 2009 Sep; Vol. 11 (9), pp. 921-33. - Publication Year :
- 2009
-
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.
- Subjects :
- Animals
Base Sequence
Carcinoma, Non-Small-Cell Lung metabolism
Carcinoma, Non-Small-Cell Lung pathology
Chromatin Immunoprecipitation
Glioma metabolism
Glioma pathology
Humans
Immunoblotting
In Situ Hybridization
Luciferases metabolism
Lung Neoplasms genetics
Lung Neoplasms metabolism
Lung Neoplasms pathology
Mice
Molecular Sequence Data
Mutation genetics
Promoter Regions, Genetic
RNA, Messenger genetics
RNA, Messenger metabolism
RNA, Small Interfering pharmacology
Rats
Response Elements genetics
Reverse Transcriptase Polymerase Chain Reaction
Transfection
Vascular Endothelial Growth Factor C antagonists & inhibitors
Vascular Endothelial Growth Factor C metabolism
Carcinoma, Non-Small-Cell Lung genetics
Gene Expression Regulation physiology
Glioma genetics
Hyperthermia, Induced
Intercellular Signaling Peptides and Proteins metabolism
Oxidative Stress
Vascular Endothelial Growth Factor C genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5586
- Volume :
- 11
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Neoplasia (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 19724686
- Full Text :
- https://doi.org/10.1593/neo.09636