Overexpression of Her-2/NEU in Epithelial Ovarian Carcinoma Induces Vascular Endothelial Growth Factor C by Activating NF-kappaB: Implications for Malignant Ascites Formation and Tumor Lymphangiogenesis.

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-kappaB, 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.