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

被引:34
作者
Hsieh, CY
Chen, CA
Chou, CH
Lai, KP
Jeng, YM
Kuo, ML
Wei, LH
机构
[1] Natl Taiwan Univ Hosp, Coll Med, Dept Oncol, Taipei 100, Taiwan
[2] Natl Taiwan Univ Hosp, Dept Obstet & Gynecol, Taipei, Taiwan
[3] Natl Taiwan Univ Hosp, Dept Pathol, Taipei 100, Taiwan
[4] Natl Taiwan Univ, Coll Med, Inst Toxicol, Lab Mol & Cellular Toxicol, Taipei, Taiwan
关键词
epithelial ovarian carcinoma; Her-2/neu; NF-kappa B; p38; vascular endothelial growth factor C;
D O I
10.1159/000076037
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
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-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. Copyright (C) 2004 National Science Council, ROC and S. Karger AG, Basel.
引用
收藏
页码:249 / 259
页数:11
相关论文
共 43 条
[31]   Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C [J].
Ristimäki, A ;
Narko, K ;
Enholm, B ;
Joukov, V ;
Alitalo, K .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (14) :8413-8418
[32]   Enhancement of cytosine arabinoside-induced apoptosis in human myeloblastic leukemia cells by NF-κB/Rel- specific decoy oligodeoxynucleotides [J].
Romano, MF ;
Lamberti, A ;
Bisogni, R ;
Tassone, P ;
Pagnini, D ;
Storti, G ;
Del Vecchio, L ;
Turco, MC ;
Venuta, S .
GENE THERAPY, 2000, 7 (14) :1234-1237
[33]   PROGNOSTIC-SIGNIFICANCE OF HER-2/NEU EXPRESSION IN ADVANCED EPITHELIAL OVARIAN-CANCER - A MULTIVARIATE-ANALYSIS [J].
RUBIN, SC ;
FINSTAD, CL ;
WONG, GY ;
ALMADRONES, L ;
PLANTE, M ;
LLOYD, KO .
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 1993, 168 (01) :162-169
[34]   Ligand-induced, receptor-mediated dimerization and activation of EGF receptor [J].
Schlessinger, J .
CELL, 2002, 110 (06) :669-672
[35]   PIK3CA is implicated as an oncogene in ovarian cancer [J].
Shayesteh, L ;
Lu, YL ;
Kuo, WL ;
Baldocchi, R ;
Godfrey, T ;
Collins, C ;
Pinkel, D ;
Powell, B ;
Mills, GB ;
Gray, JW .
NATURE GENETICS, 1999, 21 (01) :99-102
[36]   STUDIES OF THE HER-2/NEU PROTO-ONCOGENE IN HUMAN-BREAST AND OVARIAN-CANCER [J].
SLAMON, DJ ;
GODOLPHIN, W ;
JONES, LA ;
HOLT, JA ;
WONG, SG ;
KEITH, DE ;
LEVIN, WJ ;
STUART, SG ;
UDOVE, J ;
ULLRICH, A ;
PRESS, MF .
SCIENCE, 1989, 244 (4905) :707-712
[37]   Up-regulation of vascular endothelial growth factor C in breast cancer cells by heregulin-β1 [J].
Tsai, PW ;
Shiah, SG ;
Lin, MT ;
Wu, CW ;
Kuo, ML .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (08) :5750-5759
[38]   Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice [J].
Veikkola, T ;
Jussila, L ;
Makinen, T ;
Karpanen, T ;
Jeltsch, M ;
Petrova, TV ;
Kubo, H ;
Thurston, G ;
McDonald, DM ;
Achen, MG ;
Stacker, SA ;
Alitalo, K .
EMBO JOURNAL, 2001, 20 (06) :1223-1231
[39]  
Xu Y, 1995, CLIN CANCER RES, V1, P1223
[40]   ErbB2 overexpression correlates with increased expression of vascular endothelial growth factors A, C, and D in human breast carcinoma [J].
Yang, WT ;
Klos, K ;
Yang, Y ;
Smith, TL ;
Shi, DR ;
Yu, DH .
CANCER, 2002, 94 (11) :2855-2861