Overexpression of Her-2/NEU in epithelial ovarian carcinoma induces vascular endothelial growth factor C by activating NF-kappa B: implications for malignant ascites formation and tumor lymphangiogenesis.

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-kappa B, 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.

• Authors: Chang-Yao Hsieh, Chi-An Chen, Chia-Hung Chou, Kuo-Pao Lai, Yung-Ming Jeng, Min-Liang Kuo, Lin-Hung Wei
• Journal: Journal of biomedical science (J Biomed Sci) 2004 Mar-Apr Vol. 11 Issue 2 Pg. 249-59 ISSN: 1021-7770 [Print] England
• PMID: 14966375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2004 National Science Council, ROC and S. Karger AG, Basel

Chemical References

• NF-kappa B
• Vascular Endothelial Growth Factor C
• Receptor, ErbB-2
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Ascites (pathology)
• Capillary Permeability
• Cell Line, Tumor
• Cells, Cultured
• Coculture Techniques
• Endothelium, Vascular (cytology)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphangiogenesis
• Mitogen-Activated Protein Kinases (physiology)
• NF-kappa B (metabolism)
• Neoplasm Invasiveness
• Ovarian Neoplasms (chemistry, pathology)
• Receptor, ErbB-2 (analysis, physiology)
• Signal Transduction
• Transcription, Genetic
• Transfection
• Umbilical Veins (cytology)
• Vascular Endothelial Growth Factor C (analysis, biosynthesis, physiology)
• p38 Mitogen-Activated Protein Kinases