Transcriptional Regulation of Vascular Endothelial Growth Factor C by Oxidative and Thermal Stress Is Mediated by Lens Epithelium-Derived Growth Factor/p75

• Main Authors: Batya Cohen, Yoseph Addadi, Stav Sapoznik, Gila Meir, Vyacheslav Kalchenko, Alon Harmelin, Shifra Ben-Dor, Michal Neeman
• Format: Article
• Language: English
• Published: Elsevier 2009-09-01
• Series: Neoplasia: An International Journal for Oncology Research
• Online Access: http://www.sciencedirect.com/science/article/pii/S1476558609800456
• ISSN: 1476-5586; 1522-8002

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.