Journal Article

C/EBP-δ regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1α

Yang, L, Boelte, K, Min, Y, Li, J, Lin, P C, Ghose, S

2011

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/200 / 631/250/1617/290 / 631/67/322 / 692/699/67/1612 / Animals / Apoptosis / Autocrine Communication / Autocrine signalling / Biological and medical sciences / Bone marrow / Bone tumors / Carcinoma / CCAAT-Enhancer-Binding Protein-delta - deficiency / CCAAT-Enhancer-Binding Protein-delta - genetics / CCAAT-Enhancer-Binding Protein-delta - metabolism / CCAAT/enhancer-binding protein / Cell Biology / Cell Hypoxia / Cell Line, Tumor / Cell migration / Cell physiology / Cell survival / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Development and progression / Endothelial cells / Endothelial Cells - metabolism / Endothelial Cells - pathology / Female / Fundamental and applied biological sciences. Psychology / Gene Deletion / Gene Expression Regulation, Neoplastic / Human Genetics / Humans / Hypoxia-inducible factor 1 alpha / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-inducible factor 1a / Internal Medicine / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Lung Neoplasms - physiopathology / Lymphangiogenesis / Lymphangioma / Medical sciences / Medicine / Medicine & Public Health / Metastases / Metastasis / Mice / Molecular and cellular biology / Motility / Neoplasm Metastasis / Oncology / original-article / Physiological aspects / Pneumology / Substrate Specificity / Transcription factors / Tumors / Tumors of the respiratory system and mediastinum / Vascular endothelial growth factor / Vascular Endothelial Growth Factor C - genetics / Vascular Endothelial Growth Factor C - metabolism / Vascular Endothelial Growth Factor Receptor-3 - genetics / Vascular Endothelial Growth Factor Receptor-3 - metabolism / Vascular endothelial growth factor receptors