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

  1. Author:
    Min, Y.
    Ghose, S.
    Boelte, K.
    Li, J.
    Yang, L.
    Lin, P. C.

  2. Author Address

    [Min, Y.; Yang, L.; Lin, P. C.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Ghose, S.; Li, J.] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN USA. [Boelte, K.] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN USA.;Lin, PC (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, 1050 Boyles St,Bldg 560,Room 12-89, Frederick, MD 21702 USA;p.lin@nih.edu
    1. Year: 2011
    2. Date: Dec
  2. Journal: Oncogene
    1. 30
    2. 49
    3. Pages: 4901-4909
  4. Type of Article: Article
  5. ISSN: 0950-9232
  1. Abstract:

    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-1 alpha expression. Blocking HIF-1 alpha 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. Oncogene (2011) 30, 4901-4909; doi:10.1038/onc.2011.187; published online 13 June 2011

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  2. DOI: 10.1038/onc.2011.187
  3. View record in Web of Science®
  4. WOS: 000298346400006

Library Notes

  1. Fiscal Year: FY2011-2012
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