https://scholars.lib.ntu.edu.tw/handle/123456789/458254
標題: | 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 | 作者: | CHANG-YAO HSIEH CHI-AN CHEN Chou C.-H Lai K.-P YUNG-MING JENG Kuo M.-L LING-HUNG WEI |
公開日期: | 2004 | 卷: | 11 | 期: | 2 | 起(迄)頁: | 249-259 | 來源出版物: | Journal of Biomedical Science | 摘要: | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/458254 | ISSN: | 1021-7770 | DOI: | 10.1159/000076037 | SDG/關鍵字: | 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 |
顯示於: | 醫學系 |
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