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
Journal
Journal of Biomedical Science
Journal Volume
11
Journal Issue
2
Pages
249-259
Date Issued
2004
Author(s)
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. Copyright ? 2004 National Science Council, ROC and S. Karger AG, Basel.
SDGs
Other Subjects
immunoglobulin enhancer binding protein; messenger RNA; monoclonal antibody; trastuzumab; vasculotropin C; article; ascites; clinical article; controlled study; cytoplasm; disease association; disease course; drug inhibition; female; gene expression; gene overexpression; human; human tissue; immunohistochemistry; oncogene neu; ovary carcinoma; priority journal; protein expression; regulatory mechanism; signal transduction; transcription initiation; Ascites; Capillary Permeability; Cell Line, Tumor; Cells, Cultured; Coculture Techniques; Endothelium, Vascular; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphangiogenesis; Mitogen-Activated Protein Kinases; Neoplasm Invasiveness; NF-kappa B; Ovarian Neoplasms; p38 Mitogen-Activated Protein Kinases; Receptor, erbB-2; Signal Transduction; Transcription, Genetic; Transfection; Umbilical Veins; Vascular Endothelial Growth Factor C; Martes pennanti
Type
journal article