title: 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.
authors.affiliation: Division of Hematology, University of Calgary, Calgary, Canada.
authors.forename: Paola
authors.initials: P
authors.lastname: Neri
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
authors.forename: Matthew
authors.initials: M
authors.lastname: Brentnall
authors.forename: Kathy
authors.initials: K
authors.lastname: Gratton
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Klimowicz
authors.forename: Charles
authors.initials: C
authors.lastname: Lin
authors.forename: Peter
authors.initials: P
authors.lastname: Duggan
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.forename: Adnan
authors.initials: A
authors.lastname: Mansoor
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Stewart
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.forename: Nizar J
authors.initials: NJ
authors.lastname: Bahlis
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism*; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D033581:Stem Cell Transplantation; D058207:Sumoylation / Q000187:drug effects / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014182:Transplantation, Autologous; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001897:Boronic Acids; C515255:CXCL12 protein, human; D015820:Cadherins; D054377:Chemokine CXCL12; D005353:Fibronectins; D039641:Integrin beta Chains; C495607:MAF protein, human; D051257:Proto-Oncogene Proteins c-maf; D011719:Pyrazines; C107953:RAC1 protein, human; C498143:RELA protein, human; D051996:Transcription Factor RelA; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C091368:integrin beta7; D000069286:Bortezomib; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D020830:rac1 GTP-Binding Protein; D008558:Melphalan