Up-regulation of vascular endothelial growth factor C in breast cancer cells by heregulin-beta 1. A critical role of p38/nuclear factor-kappa B signaling pathway.

Abstract

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-beta 1 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-beta 1-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-beta 1. NF-kappa B has been shown to be probably involved in interleukin-1 beta- or tumor necrosis factor-alpha-induced VEGF-C mRNA expression in human fibroblasts. Here we found that HRG-beta 1 could stimulate NF-kappa B nuclear translocation and DNA-binding activity via the I kappa B alpha phosphorylation-degradation mechanism. Blockage of the NF-kappa B activation cascade caused a complete inhibition of the HRG-beta 1-induced elevation of VEGF-C. In promoter-reporter assay, the luciferase activities of the reporter constructs, including the putative NF-kappa B site deleted and mutated form were significantly reduced after HRG-beta 1 treatment as compared with the 1.5-kb VEGF-C promoter. Although investigating the upstream kinase pathway(s) involved in HRG-beta 1-elicited NF-kappa B activation and VEGF-C up-regulation, we found that HRG-beta1 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-beta 1. A similar inhibition in VEGF-C expression was obtained by cell transfection with dominant-negative p38 (p38AF). Interestingly, the HRG-beta 1-induced NF-kappa B activation cascade was also effectively blocked by SB203580 treatment or p38AF transfection. Our data thus suggests that HRG-beta 1 stimulated a NF-kappa B-dependent up-regulation of VEGF-C through the p38 MAPK signaling pathway in human breast cancer cells.

• Authors: Pei-Wen Tsai, Shine-Gwo Shiah, Ming-Tsan Lin, Cheng-Wen Wu, Min-Liang Kuo
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 8 Pg. 5750-9 (Feb 21 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12471041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelial Growth Factors
• NF-kappa B
• Neuregulin-1
• RNA, Messenger
• Vascular Endothelial Growth Factor C
• heregulin beta1
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Breast (drug effects, physiology)
• Breast Neoplasms (physiopathology)
• Endothelial Growth Factors (genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Neuregulin-1 (pharmacology)
• Protein Biosynthesis
• RNA, Messenger (genetics)
• Signal Transduction (physiology)
• Transcription, Genetic
• Vascular Endothelial Growth Factor C
• p38 Mitogen-Activated Protein Kinases