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Overexpression of progelatinase B/proMMP-9 affects migration regulatory pathways and impairs chronic lymphocytic leukemia cell homing to bone marrow and spleen.

Journal of leukocyte biology (2014-08-01)
Elvira Bailón, Estefanía Ugarte-Berzal, Irene Amigo-Jiménez, Philippe Van den Steen, Ghislain Opdenakker, José A García-Marco, Angeles García-Pardo
ABSTRACT

This study addresses the role of (pro)MMP-9 overexpression in CLL cell migration. We have used primary CLL cells and CLL-derived MEC-1 cells transfected with empty (mock cells) or proMMP-9-encoding (MMP-9 cells) lentiviral vectors. The constitutive (pro)MMP-9 expression in mock cells and primary CLL cells was similar, whereas in MMP-9 cells, expression resembled that of CLL cells incubated with proMMP-9. In xenograft models, in NOD/SCID mice, MMP-9-MEC-1 transfectants showed significantly reduced homing to bone marrow and spleen compared with mock cells. Likewise, incubation of primary CLL cells with proMMP-9, before injection into mice, inhibited their homing to these organs. This inhibition was specific, dose-dependent, and observed in all CLL tested, independently of prognostic markers or disease stage. Additionally, the MMP-9 catalytic activity was only partially involved, as the inactive mutant proMMP-9MutE had a partial effect. MMP-9 cells also showed impaired migration in vitro, which was reverted by reducing (pro)MMP-9 expression with siRNAs. CLL migration thus requires optimal (pro)MMP-9 expression levels, below or above which migration is hampered. Biochemical analysis of the (pro)MMP-9 effect indicated that MMP-9 cells or primary CLL cells incubated with proMMP-9 had reduced activation of migration regulatory molecules, including RhoAGTPase, Akt, ERK, and FAK. In contrast, p190RhoGAP (RhoA inhibitor) and PTEN (Akt/ERK/FAK inhibitor) were up-regulated in MMP-9 cells. Reduction of (pro)MMP-9 expression by siRNAs restored RhoA activity and diminished PTEN levels. Our results reveal a novel function for (pro)MMP-9 in modulating signaling pathways leading to CLL cell arrest. Therefore, local high (pro)MMP-9 expression may contribute to malignant cell retention in lymphoid organs and disease progression.

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