Integrin β7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion.

Abstract:

:Integrin-β7 (ITGB7) mRNA is detected in multiple myeloma (MM) cells and its presence is correlated with MAF gene activation. Although the involvement of several integrin family members in MM-stoma cell interaction is well documented, the specific biologic functions regulated by integrin-β7 in MM are largely unknown. Clinically, we have correlated integrin-β7 expression in MM with poor survival outcomes post autologous stem cell transplantation and postsalvage therapy with bortezomib. Functionally, we have found that shRNA-mediated silencing of ITGB7 reduces MM-cell adhesion to extra-cellular matrix elements (fibronectin, E-cadherin) and reverses cell-adhesion-mediated drug resistance (CAM-DR) sensitizing them to bortezomib and melphalan. In addition, ITGB7 silencing abrogated MM-cell transwell migration in response to SDF1α gradients, reduced vessel density in xenografted tumors, and altered MM cells in vivo homing into the BM. Mechanistically, ITGB7 knockdown inhibited focal adhesion kinase (FAK) and Src phosphorylation, Rac1 activation, and SUMOylation, reduced VEGF production in MM-BM stem cell cocultures and attenuated p65-NF-κB activity. Our findings support a role for integrin-β7 in MM-cell adhesion, migration, and BM homing, and pave the way for a novel therapeutic approach targeting this molecule.

journal_name

Blood

journal_title

Blood

authors

Neri P,Ren L,Azab AK,Brentnall M,Gratton K,Klimowicz AC,Lin C,Duggan P,Tassone P,Mansoor A,Stewart DA,Boise LH,Ghobrial IM,Bahlis NJ

doi

10.1182/blood-2010-06-292243

subject

Has Abstract

pub_date

2011-06-09 00:00:00

pages

6202-13

issue

23

eissn

0006-4971

issn

1528-0020

pii

blood-2010-06-292243

journal_volume

117

pub_type

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