title: Bone marrow stromal cells protect myeloma cells from bortezomib induced apoptosis by suppressing microRNA-15a expression.
abstract: Despite unsurpassed anti-tumor activity of bortezomib for multiple myeloma (MM), drug resistance has emerged as a challenge, especially when MM cells adhere to the stroma. This study aimed to determine whether bone marrow stromal cells (BMSCs) have a role in the development of chemoresistance in MM. Our data demonstrate that the secretion of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and cell-to-cell contact with microenvironment-derived stromal cells from patients with multiple myeloma (MM-BMSCs) significantly decreased the sensitivity of myeloma cells to bortezomib treatment. Mechanistically, we found that microRNA (miRNA)- 15a expression was up-regulated in U266 and NCI-H929 cells treated by bortezomib, which was inhibited by MM-BMSCs. miRNA-15a transfected myeloma cells were arrested in G1/S checkpoint and secreted less VEGF compared to control transfected cells, although no significant difference was found in VEGF mRNA levels. In conclusion, our data suggest that via suppressing miRNA-15a expression, BMSCs provide survival support and protect myeloma cells from bortezomib induced apoptosis.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
authors.forename: Mu
authors.initials: M
authors.lastname: Hao
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: An
authors.forename: Hengxing
authors.initials: H
authors.lastname: Meng
authors.forename: Youjin
authors.initials: Y
authors.lastname: Han
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Xie
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yu
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Lugui
authors.initials: L
authors.lastname: Qiu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D017154:Stromal Cells / Q000378:metabolism; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001897:Boronic Acids; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; D011719:Pyrazines; D042461:Vascular Endothelial Growth Factor A; D000069286:Bortezomib