| First Author | Min Y | Year | 2011 |
| Journal | Oncogene | Volume | 30 |
| Issue | 49 | Pages | 4901-9 |
| PubMed ID | 21666710 | Mgi Jnum | J:178569 |
| Mgi Id | MGI:5299287 | Doi | 10.1038/onc.2011.187 |
| Citation | Min Y, et al. (2011) C/EBP-delta regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1alpha. Oncogene 30(49):4901-9 |
| abstractText | CCAAT/enhancer-binding protein-delta (C/EBP-delta), a transcription factor, is elevated in carcinoma compared with that in normal tissue. This study reports a novel function of C/EBP-delta in lymphangiogenesis and tumor metastasis. Genetic deletion of C/EBP-delta in mice resulted in a significant reduction of lymphangiogenesis and pulmonary metastases, with a dramatic reduction of vascular endothelial growth factor-C (VEGF-C) and its cognate receptor VEGF receptor-3 (VEGFR3) in lymphatic endothelial cells (LECs). By contrast, no difference of VEGF-C in tumor tissues and bone marrow was observed between null and wild-type mice. Consistently, forced expression of C/EBP-delta increased VEGF-C and VEGFR3 expression in cultured LECs. These findings suggest a specific and important role of C/EBP-delta in the regulation of VEGFR3 signaling in LECs. Furthermore, expression of C/EBP-delta in cultured LECs significantly increased cell motility, and knockdown of C/EBP-delta inhibited cell motility and lymphatic vascular network formation in vitro. Forced expression of VEGF-C, but not recombinant VEGF-C, rescued the knockdown of C/EBP-delta-induced cell apoptosis, indicative of autonomous VEGF-C autocrine signaling essential for LEC survival. Moreover, hypoxia induces C/EBP-delta expression and C/EBP-delta regulates HIF-1alpha expression. Blocking HIF-1alpha activity totally blocked CEBP-delta-induced VEGF-C and VEGFR3 expression in LECs. Together, these findings uncover a new function of CEBP-delta in lymphangiogenesis through regulation of VEGFR3 signaling in LECs. |
