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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

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Journal of Biomedical Science

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.

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Authors and Affiliations

  1. Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taiwan, ROC

    Chang-Yao Hsieh, Kuo-Pao Lai & Lin-Hung Wei

  2. Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taiwan, ROC

    Chi-An Chen

  3. Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taiwan, ROC

    Yung-Ming Jeng

  4. Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan, ROC

    Chia-Hung Chou & Min-Liang Kuo

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Hsieh, CY., Chen, CA., Chou, CH. et al. 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. J Biomed Sci 11, 249–259 (2004). https://doi.org/10.1007/BF02256568

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  • DOI: https://doi.org/10.1007/BF02256568

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