Author:

Keywords:

B-Lymphocytes, Cell Movement, Cells, Cultured, Down-Regulation, Endothelial Cells, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Matrix Metalloproteinase 9, RNA, Small Interfering, STAT1 Transcription Factor, Umbilical Veins, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Science & Technology, Life Sciences & Biomedicine, Hematology, ENDOTHELIAL GROWTH-FACTOR, ALPHA-4-BETA-1 INTEGRIN, AUTOCRINE VEGF, CLL, ANGIOGENESIS, SUPPRESSION, INVASION, GAMMA, MMP-9, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, Immunology, 3101 Biochemistry and cell biology, 3201 Cardiovascular medicine and haematology, 3213 Paediatrics

Abstract:

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.