https://scholars.lib.ntu.edu.tw/handle/123456789/477525
標題: | Up-regulation of vascular endothelial growth factor C in breast cancer cells by heregulin-β1: A critical role of p38/nuclear factor-κB signaling pathway | 作者: | Tsai P.-W. Shiah S.-G. MING-TSAN LIN Wu C.-W. Kuo M.-L. |
公開日期: | 2003 | 卷: | 278 | 期: | 8 | 起(迄)頁: | 5750-5759 | 來源出版物: | Journal of Biological Chemistry | 摘要: | Vascular endothelial growth factor C (VEGF-C) is a critical activator of tumor lymphangiogenesis that recently has been strongly implicated in the tumor metastasis process. In this study, we identified that HRG-β1 stimulated up-regulation of VEGF-C mRNA and protein of human breast cancer cells in a dosage- and time-dependent manner and that this up-regulation was de novo RNA synthesis-dependent. The HRG-β1-induced increase in VEGF-C expression was effectively reduced by treatment with Herceptin, an antibody specifically against HER2. Also, when HER2 was overexpressed in MCF-7 cells that resulted in an evident increase in the VEGF-C level, suggesting an essential role of HER2 in mediating VEGF-C up-regulation by HRG-β1. NF-κB has been shown to be probably involved in interleukin-1β- or tumor necrosis factor-α-induced VEGF-C mRNA expression in human fibroblasts. Here we found that HRG-β1 could stimulate NF-κB nuclear translocation and DNA-binding activity via the IκBα phosphorylation-degradation mechanism. Blockage of the NF-κB activation cascade caused a complete inhibition of the HRG-β1-induced elevation of VEGF-C. In promoter-reporter assay, the luciferase activities of the reporter constructs, including the putative NF-κB site deleted and mutated form were significantly reduced after HRG-β1 treatment as compared with the 1.5-kb VEGF-C promoter. Although investigating the upstream kinase pathway(s) involved in HRG-β1-elicited NF-κB activation and VEGF-C up-regulation, we found that HRG-β1 could activate extracellular signal-regulated protein kinase 1/2, phosphatidylinositol 3′-kinase, and p38 mitogen-activated protein kinase (MAPK) in MCF-7. However, only SB203580 (a specific inhibitor of p38 MAPK), not PD98059 nor LY294002, blocked the up-regulation of VEGF-C by HRG-β1. A similar inhibition in VEGF-C expression was obtained by cell transfection with dominant-negative p38 (p38AF). Interestingly, the HRG-β1-induced NF-κB activation cascade was also effectively blocked by SB203580 treatment or p38AF transfection. Our data thus suggests that HRG-β1 stimulated a NF-κB-dependent up-regulation of VEGF-C through the p38 MAPK signaling pathway in human breast cancer cells. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-0037458645&doi=10.1074%2fjbc.M204863200&partnerID=40&md5=8be48c2143dd39a74f85fad089aea521 https://scholars.lib.ntu.edu.tw/handle/123456789/477525 |
ISSN: | 0021-9258 | DOI: | 10.1074/jbc.M204863200 | SDG/關鍵字: | DNA; Proteins; RNA; Tumors; Breast cancer; Biochemistry; 2 (2 amino 3 methoxyphenyl)chromone; 2 morpholino 8 phenylchromone; 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole; heregulin beta1; I kappa B alpha; immunoglobulin enhancer binding protein; luciferase; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase inhibitor; mutant protein; neu differentiation factor; phosphatidylinositol 3 kinase; RNA; trastuzumab; tumor necrosis factor alpha; unclassified drug; vasculotropin C; endothelial cell growth factor; immunoglobulin enhancer binding protein; messenger RNA; mitogen activated protein kinase; mitogen activated protein kinase p38; neu differentiation factor; vasculotropin C; article; breast cancer; cell strain MCF 7; controlled study; enzyme activity; gene construct; gene expression; genetic transfection; human; human cell; priority journal; promoter region; protein analysis; protein expression; reporter gene; RNA analysis; RNA synthesis; signal transduction; upregulation; breast; breast tumor; drug effect; female; gene expression regulation; genetic transcription; genetics; metabolism; pathophysiology; physiology; protein synthesis; signal transduction; Mink cell focus-forming virus; Breast; Breast Neoplasms; Endothelial Growth Factors; Female; Gene Expression Regulation, Neoplastic; Humans; Mitogen-Activated Protein Kinases; Neuregulin-1; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Protein Biosynthesis; RNA, Messenger; Signal Transduction; Transcription, Genetic; Vascular Endothelial Growth Factor C |
顯示於: | 醫學系 |
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