Hsieh Chang-Yao, Chen Chi-An, Chou Chia-Hung, Lai Kuo-Pao, Jeng Yung-Ming, Kuo Min-Liang, Wei Lin-Hung
Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, ROC.
J Biomed Sci. 2004 Mar-Apr;11(2):249-59. doi: 10.1007/BF02256568.
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.
血管内皮生长因子C（VEGF-C）是一种重要的生长因子，它控制着与上皮性卵巢癌相关的腹腔内肿瘤的淋巴扩散和发展；然而，其调控机制尚不清楚。Her-2/NEU的过表达与晚期上皮性卵巢癌患者的不良生存相关。因此，本研究试图分析卵巢癌中Her-2/NEU癌基因与VEGF-C之间的关联，并阐明Her-2/NEU诱导VEGF-C的分子机制。采用免疫组织化学法检测41例上皮性卵巢癌患者组织中Her-2/NEU和VEGF-C的表达。使用几种Her-2/NEU稳定转染的Caov-3卵巢癌细胞来评估Her-2/NEU对VEGF-C的影响、可能的调控机制以及VEGF-C的生物学功能。我们的实验结果表明，Her-2/NEU癌基因与上皮性卵巢癌患者（p < 0.05；Fisher精确检验）及体外细胞系中VEGF-C的表达之间存在显著关联。Caov-3卵巢癌细胞中Her-2/NEU的过表达导致大量VEGF-C mRNA和蛋白的诱导；这一过程被赫赛汀剂量依赖性抑制。VEGF-C的产生显著增加了内皮通透性。药理学和基因抑制试验表明，细胞质信号分子p38 MAPK和转录因子NF-κB在Her-2/NEU对VEGF-C基因的转录激活中起关键作用。总之，这项工作明确表明Her-2/NEU癌基因对于卵巢癌中VEGF-C的调控至关重要。使用靶向Her-2/NEU受体的单克隆抗体可能有助于限制卵巢癌中恶性腹水的形成和淋巴转移。
