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

Oncogene volume 30, pages 4901–4909 (2011)Cite this article

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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.

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Acknowledgements

This work was supported in part by grants from NIH (CA108856, NS45888 and AR053718).

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  1. Y Min and S Ghose: These authors contributed equally to this work.

Authors and Affiliations

  1. Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA

    Y Min, L Yang & P C Lin

  2. Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    S Ghose & J Li

  3. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    K Boelte

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  1. Y Min
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Correspondence to P C Lin.

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Min, Y., Ghose, S., Boelte, K. et al. C/EBP-δ regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1α. Oncogene 30, 4901–4909 (2011). https://doi.org/10.1038/onc.2011.187

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