title: C/EBP-δ regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1α.
abstract: CCAAT/enhancer-binding protein-δ (C/EBP-δ), a transcription factor, is elevated in carcinoma compared with that in normal tissue. This study reports a novel function of C/EBP-δ in lymphangiogenesis and tumor metastasis. Genetic deletion of C/EBP-δ 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-δ increased VEGF-C and VEGFR3 expression in cultured LECs. These findings suggest a specific and important role of C/EBP-δ in the regulation of VEGFR3 signaling in LECs. Furthermore, expression of C/EBP-δ in cultured LECs significantly increased cell motility, and knockdown of C/EBP-δ 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-δ-induced cell apoptosis, indicative of autonomous VEGF-C autocrine signaling essential for LEC survival. Moreover, hypoxia induces C/EBP-δ expression and C/EBP-δ regulates HIF-1α expression. Blocking HIF-1α activity totally blocked CEBP-δ-induced VEGF-C and VEGFR3 expression in LECs. Together, these findings uncover a new function of CEBP-δ in lymphangiogenesis through regulation of VEGFR3 signaling in LECs.
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Min
authors.forename: S
authors.initials: S
authors.lastname: Ghose
authors.forename: K
authors.initials: K
authors.lastname: Boelte
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: P C
authors.initials: PC
authors.lastname: Lin
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D042583:Lymphangiogenesis; D051379:Mice; D009362:Neoplasm Metastasis; D013379:Substrate Specificity; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042582:Vascular Endothelial Growth Factor C; D051743:CCAAT-Enhancer-Binding Protein-delta; D040321:Vascular Endothelial Growth Factor Receptor-3