PMID- 21474670
OWN - NLM
STAT- MEDLINE
DCOM- 20110812
LR  - 20211020
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 117
IP  - 23
DP  - 2011 Jun 9
TI  - Integrin beta7-mediated regulation of multiple myeloma cell adhesion, migration, and 
      invasion.
PG  - 6202-13
LID - 10.1182/blood-2010-06-292243 [doi]
AB  - Integrin-beta7 (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-beta7 in MM are largely 
      unknown. Clinically, we have correlated integrin-beta7 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 SDF1alpha 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-kappaB activity. Our 
      findings support a role for integrin-beta7 in MM-cell adhesion, migration, and BM 
      homing, and pave the way for a novel therapeutic approach targeting this 
      molecule.
FAU - Neri, Paola
AU  - Neri P
AD  - Division of Hematology, University of Calgary, Calgary, Canada.
FAU - Ren, Li
AU  - Ren L
FAU - Azab, Abdel Kareem
AU  - Azab AK
FAU - Brentnall, Matthew
AU  - Brentnall M
FAU - Gratton, Kathy
AU  - Gratton K
FAU - Klimowicz, Alexander C
AU  - Klimowicz AC
FAU - Lin, Charles
AU  - Lin C
FAU - Duggan, Peter
AU  - Duggan P
FAU - Tassone, Pierfrancesco
AU  - Tassone P
FAU - Mansoor, Adnan
AU  - Mansoor A
FAU - Stewart, Douglas A
AU  - Stewart DA
FAU - Boise, Lawrence H
AU  - Boise LH
FAU - Ghobrial, Irene M
AU  - Ghobrial IM
FAU - Bahlis, Nizar J
AU  - Bahlis NJ
LA  - eng
GR  - R01 CA125690/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110407
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Boronic Acids)
RN  - 0 (CXCL12 protein, human)
RN  - 0 (Cadherins)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Fibronectins)
RN  - 0 (Integrin beta Chains)
RN  - 0 (MAF protein, human)
RN  - 0 (Proto-Oncogene Proteins c-maf)
RN  - 0 (Pyrazines)
RN  - 0 (RAC1 protein, human)
RN  - 0 (RELA protein, human)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (integrin beta7)
RN  - 69G8BD63PP (Bortezomib)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (PTK2 protein, human)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
RN  - Q41OR9510P (Melphalan)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Alkylating/pharmacology
MH  - Bone Marrow Cells/metabolism/pathology
MH  - Boronic Acids/pharmacology
MH  - Bortezomib
MH  - Cadherins/genetics/metabolism
MH  - Cell Adhesion/drug effects/genetics
MH  - Cell Line, Tumor
MH  - *Cell Movement
MH  - Chemokine CXCL12/genetics/metabolism
MH  - Coculture Techniques
MH  - Drug Resistance, Neoplasm/drug effects/genetics
MH  - Fibronectins/genetics/metabolism
MH  - Focal Adhesion Kinase 1/genetics/metabolism
MH  - Gene Knockdown Techniques
MH  - Gene Silencing
MH  - Humans
MH  - Integrin beta Chains/genetics/*metabolism
MH  - Melphalan/pharmacology
MH  - Mice
MH  - Multiple Myeloma/genetics/*metabolism/pathology/therapy
MH  - Neoplasm Invasiveness
MH  - Neoplasm Transplantation
MH  - Phosphorylation/drug effects/genetics
MH  - Proto-Oncogene Proteins c-maf/genetics/metabolism
MH  - Pyrazines/pharmacology
MH  - Stem Cell Transplantation
MH  - Sumoylation/drug effects/genetics
MH  - Transcription Factor RelA/genetics/metabolism
MH  - Transplantation, Autologous
MH  - Transplantation, Heterologous
MH  - Vascular Endothelial Growth Factor A/biosynthesis/genetics
MH  - rac1 GTP-Binding Protein/genetics/metabolism
MH  - src-Family Kinases/genetics/metabolism
PMC - PMC3122944
EDAT- 2011/04/09 06:00
MHDA- 2011/08/13 06:00
PMCR- 2012/06/09
CRDT- 2011/04/09 06:00
PHST- 2011/04/09 06:00 [entrez]
PHST- 2011/04/09 06:00 [pubmed]
PHST- 2011/08/13 06:00 [medline]
PHST- 2012/06/09 00:00 [pmc-release]
AID - S0006-4971(20)44963-8 [pii]
AID - 2010/292243 [pii]
AID - 10.1182/blood-2010-06-292243 [doi]
PST - ppublish
SO  - Blood. 2011 Jun 9;117(23):6202-13. doi: 10.1182/blood-2010-06-292243. Epub 2011 
      Apr 7.