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
Bloodjournal_title
Bloodauthors
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 NJdoi
10.1182/blood-2010-06-292243subject
Has Abstractpub_date
2011-06-09 00:00:00pages
6202-13issue
23eissn
0006-4971issn
1528-0020pii
blood-2010-06-292243journal_volume
117pub_type
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