Integrin β7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion.
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.
Mesh Terms:
Animals, Antineoplastic Agents, Alkylating, Bone Marrow Cells, Boronic Acids, Cadherins, Cell Adhesion, Cell Line, Tumor, Cell Movement, Chemokine CXCL12, Coculture Techniques, Drug Resistance, Neoplasm, Fibronectins, Focal Adhesion Kinase 1, Gene Knockdown Techniques, Gene Silencing, Humans, Integrin beta Chains, Melphalan, Mice, Multiple Myeloma, Neoplasm Invasiveness, Neoplasm Transplantation, Phosphorylation, Proto-Oncogene Proteins c-maf, Pyrazines, Stem Cell Transplantation, Sumoylation, Transcription Factor RelA, Transplantation, Autologous, Transplantation, Heterologous, Vascular Endothelial Growth Factor A, rac1 GTP-Binding Protein, src-Family Kinases
Animals, Antineoplastic Agents, Alkylating, Bone Marrow Cells, Boronic Acids, Cadherins, Cell Adhesion, Cell Line, Tumor, Cell Movement, Chemokine CXCL12, Coculture Techniques, Drug Resistance, Neoplasm, Fibronectins, Focal Adhesion Kinase 1, Gene Knockdown Techniques, Gene Silencing, Humans, Integrin beta Chains, Melphalan, Mice, Multiple Myeloma, Neoplasm Invasiveness, Neoplasm Transplantation, Phosphorylation, Proto-Oncogene Proteins c-maf, Pyrazines, Stem Cell Transplantation, Sumoylation, Transcription Factor RelA, Transplantation, Autologous, Transplantation, Heterologous, Vascular Endothelial Growth Factor A, rac1 GTP-Binding Protein, src-Family Kinases
Blood
Date: Jun. 09, 2011
PubMed ID: 21474670
View in: Pubmed Google Scholar
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