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Journal of Biomedical Science

, Volume 11, Issue 2, pp 249–259 | Cite as

Overexpression of Her-2/neu in epithelial ovarian carcinoma induces vascular endothelial growth factor C by activating NF-κB: Implications for malignant ascites formation and tumor lymphangiogenesis

  • Chang-Yao Hsieh
  • Chi-An Chen
  • Chia-Hung Chou
  • Kuo-Pao Lai
  • Yung-Ming Jeng
  • Min-Liang Kuo
  • Lin-Hung Wei
Original Paper

Abstract

Vascular endothelial growth factor C (VEGF-C) is an important growth factor that governs lymphatic spread and the development of intraperitoneal tumors associated with epithelial ovarian cancer; however, its regulation is not yet understood. Overexpression of Her-2/neu is related to poor survival in advanced epithelial ovarian carcinoma patients. Accordingly, this study attempted to analyze the association between the Her-2/neu oncogene and VEGF-C in ovarian carcinoma and to elucidate the molecular mechanism of VEGF-C induction by Her-2/neu. Immunohistochemistry was used to determine the expression of Her-2/neu and VEGF-C in tissues from 41 patients with epithelial ovarian carcinoma. Several Her-2/neu-stably-transfected Caov-3 ovarian carcinoma cells were used to evaluate the effect of Her-2/neu on VEGF-C, the possible regulation mechanism, and the biological function of VEGF-C. Our experimental results identified a significant association between the Her-2/neu oncogene and VEGF-C expression in both epithelial ovarian cancer patients (p < 0.05; Fisher's exact test) and in vitro cell lines. The overexpression of Her-2/neu in Caov-3 ovarian cancer cells resulted in induction of a considerable amount of VEGF-C mRNA and protein; this process was dose-dependently inhibited by herceptin. The generation of VEGF-C significantly increased endothelial permeability. Pharmacological and genetic inhibition assays revealed that the cytoplasmic signaling molecule, p38 MAPK, and the transcriptional factor, NF-κB, are critically involved in the transcriptional activation of the VEGF-C gene by Her-2/neu. In conclusion, this work clearly establishes that the Her-2/neu oncogene is essential for the regulation of VEGF-C in ovarian carcinoma. It may be possible to use the monoclonal antibody targeting Her-2/neu receptor to limit the formation of malignant ascites and lymphatic spread in ovarian carcinoma.

Key Words

Epithelial ovarian carcinoma Her-2/neu NF-κB p38 Vascular endothelial growth factor C 

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Copyright information

© National Science Council 2004

Authors and Affiliations

  • Chang-Yao Hsieh
    • 1
  • Chi-An Chen
    • 2
  • Chia-Hung Chou
    • 4
  • Kuo-Pao Lai
    • 1
  • Yung-Ming Jeng
    • 3
  • Min-Liang Kuo
    • 4
  • Lin-Hung Wei
    • 1
  1. 1.Department of OncologyNational Taiwan University Hospital and National Taiwan University College of MedicineTaiwan, ROC
  2. 2.Department of Obstetrics and GynecologyNational Taiwan University Hospital and National Taiwan University College of MedicineTaiwan, ROC
  3. 3.Department of PathologyNational Taiwan University Hospital and National Taiwan University College of MedicineTaiwan, ROC
  4. 4.Laboratory of Molecular and Cellular Toxicology, Institute of ToxicologyNational Taiwan University College of MedicineTaipeiTaiwan, ROC

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