VEGF/VEGFR2 interaction down-regulates matrix metalloproteinase–9 via STAT1 activation and inhibits B chronic lymphocytic leukemia cell migration

• Published in: Blood 2010-01, Vol.115 (4), p.846-849
• Main Authors: Ugarte-Berzal, Estefanía, Redondo-Muñoz, Javier, Eroles, Pilar, del Cerro, Mercedes Hernández, García-Marco, José A., Terol, María José, García-Pardo, Angeles
• Format: Article
• Language: English
• Subjects: B-Lymphocytes - cytology; B-Lymphocytes - metabolism; Biological and medical sciences; Cell Movement - drug effects; Cell Movement - physiology; Cells, Cultured; Down-Regulation - drug effects; Down-Regulation - physiology; Endothelial Cells - cytology; Hematologic and hematopoietic diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Matrix Metalloproteinase 9 - metabolism; Medical sciences; RNA, Small Interfering; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Umbilical Veins - cytology; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-08-239426

B-cell chronic lymphocytic leukemia (B-CLL) migration involves several molecules, including matrix metalloproteinase–9 (MMP-9) and vascular endothelial growth factor (VEGF). We have studied whether VEGF regulates MMP-9. VEGF significantly reduced MMP-9 protein expression in a dose-dependent manner, measured by gelatin zymography. Blocking the VEGFR2 receptor restored MMP-9 levels, implicating this receptor in the observed effect. Down-regulation of MMP-9 by VEGF resulted in significant inhibition of B-CLL cell migration through Matrigel or human umbilical vein endothelial cells, confirming the crucial role of MMP-9 in these processes. Reverse-transcription polymerase chain reaction analyses revealed that VEGF regulated MMP-9 at the transcriptional level. Indeed, VEGF induced STAT1 tyrosine phosphorylation, and this was blocked by inhibiting VEGFR2. STAT1 was responsible for MMP-9 down-regulation, as STAT1 gene silencing restored MMP-9 production and B-CLL cell migration in the presence of VEGF. Thus, the levels of VEGF and MMP-9 influence B-CLL cell expansion and both molecules could constitute therapeutic targets for this disease.