Induction of miR-146a by multiple myeloma cells in mesenchymal stromal cells stimulates their pro-tumoral activity.
Mutual communication between multiple myeloma (MM) cells and mesenchymal stromal cells (MSC) plays a pivotal role in supporting MM progression. In MM, MSC exhibit a different genomic profile and dysregulated cytokine secretion compared to normal MSC, however the mechanisms involved in these changes are not fully understood. Here, we examined the miRNA changes in human MSC after culture with conditioned medium of MM cells and found 19 dysregulated miRNAs, including upregulated miR-146a. Moreover, exosomes derived from MM cells contained miR-146a and could be transferred into MSC. After overexpressing miR-146a in MSC, secretion of several cytokines and chemokines including CXCL1, IL6, IL-8, IP-10, MCP-1, and CCL-5 was elevated, resulting in the enhancement of MM cell viability and migration. DAPT, an inhibitor of the endogenous Notch pathway, was able to abrogate the miR-146a-induced increase of cytokines in MSC, suggesting the involvement of the Notch pathway. Taken together, our results demonstrate a positive feedback loop between MM cells and MSC: MM cells promote the increase of miR146a in MSC which leads to more cytokine secretion, which in turn favors MM cell growth and migration.
Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Kim
K
De Veirman
Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Jinheng
J
Wang
Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium; Department of Lung Cancer Surgery, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
Song
S
Xu
Service d'Hématologie Centre Hospitalier Universitaire (CHU), Lille, France.
Xavier
X
Leleu
Cell Differentiation Lab, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Eddy
E
Himpe
Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Ken
K
Maes
Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Elke
E
De Bruyne
Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Els
E
Van Valckenborgh
Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Karin
K
Vanderkerken
Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Eline
E
Menu
Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium; Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium. Electronic address: ivan.vanriet@uzbrussel.be.
Ivan
I
Van Riet
D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D017077:Culture Media, Conditioned / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D059016:Tumor Microenvironment; D015854:Up-Regulation
D017077:Culture Media, Conditioned; D016207:Cytokines; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D051880:Receptors, Notch
Exosomes; Mesenchymal stromal cell; Multiple myeloma; Notch pathway; miR-146a