期刊
NEOPLASIA
卷 11, 期 9, 页码 921-U271出版社
ELSEVIER SCIENCE INC
DOI: 10.1593/neo.09636
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资金
- Israel Science Foundation [93/07]
- National Institutes of Health [R01 CA75334]
- European Research Council [232640-IMAGO]
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 down-modulated 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.
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