Up-Regulation of Vascular Endothelial Growth Factor C in Breast Cancer Cells by Heregulin-Beta1: A Critical Role of P38/Nf-Kb Signaling Pathway
Resource
THE JOURNAL OF BIOLOGICAL CHEMISTRY v.278 n.8 pp.5750-5759
Journal
THE JOURNAL OF BIOLOGICAL CHEMISTRY
Journal Volume
v.278
Journal Issue
n.8
Pages
5750-5759
Date Issued
2003
Date
2003
Author(s)
SHIAH, SHINE-GWO
LIN, MING-TSAN
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-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-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-1. NF-B has been shown to be probably involved in interleukin-1- or tumor necrosis factor--induced VEGF-C mRNA expression in human fibroblasts . Here we found that HRG-1 could stimulate NF-B nuclear translocation and DNA-binding activity via the IB phosphorylation-degradation mechanism. Blockage of the NF-B activation cascade caused a complete inhibition of the HRG-1 -induced elevation of VEGF-C. In promoter-reporter assay, the luciferase activities of the reporter constructs, including the putative NF-B site deleted and mutated form were significantly reduced after HRG-1 treatment as compared with the 1.5-kb VEGF-C promoter. Although investigating the upstream kinase pathway(s) involved in HRG-1-elicited NF -B activation and VEGF-C up-regulation, we found that HRG-1 could activate extracellular signal-regulated protein kinase 1/2, phosphatidylinositol 3 '-kinase, and p38 mitogen- activated protein kinase (MAPK) in MCF-7. However, only SB 203580 (a specific inhibitor of p38 MAPK), not PD98059 nor LY294002, blocked the up-regulation of VEGF-C by HRG-1. A similar inhibition in VEGF-C expression was obtained by cell transfection with dominant-negative p38 (p38AF). Interestingly, the HRG-1-induced NF-B activation cascade was also effectively blocked by SB203580 treatment or p 38AF transfection. Our data thus suggests that HRG-1 stimulated a NF-B- dependent up-regulation of VEGF-C through the p38 MAPK signaling pathway in human breast cancer cells.
SDGs
Type
journal article