硼替佐米
间质细胞
骨髓
癌症研究
多发性骨髓瘤
MAPK/ERK通路
小RNA
肿瘤微环境
分泌物
生物
细胞生物学
信号转导
免疫学
内分泌学
肿瘤细胞
基因
生物化学
作者
Hui Zhang,Zhijiang Du,Chenggong Tu,Xiyan Zhou,Eline Menu,Jinheng Wang
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2023-09-26
卷期号:84 (1): 39-55
标识
DOI:10.1158/0008-5472.can-23-0189
摘要
Bone marrow stromal cell (BMSC)-derived small extracellular vesicles (sEV) promote drug resistance to bortezomib in multiple myeloma cells. Elucidating the components of BMSC sEV that induce drug resistance in multiple myeloma cells could help identify strategies to overcome resistance. Considering the hypoxic nature of the myeloma microenvironment, we explored the role of hypoxia in regulating BMSC sEV cargo and investigated whether hypoxia-driven sEV miRNAs contribute to the drug resistance in multiple myeloma cells. Hypoxia increased the release of sEVs from BMSCs, and these sEVs more strongly attenuated bortezomib sensitivity in multiple myeloma cells than sEVs from BMSCs under normoxic conditions. RNA sequencing revealed that significantly elevated levels of miR-140-5p and miR-28-3p were enclosed in hypoxic BMSC-derived sEVs. Both miR-140-5p and miR-28-3p conferred bortezomib resistance in multiple myeloma cells by synergistically targeting SPRED1, a member of the Sprouty protein family that regulates MAPK activation. SPRED1 inhibition reduced sensitivity to bortezomib in multiple myeloma cells through activating MAPK-related pathways and significantly promoted multiple myeloma bortezomib resistance and tumor growth in a mouse model. These findings shed light on the role of hypoxia-induced miRNAs shuttled in BMSC-derived sEVs to multiple myeloma cells in inducing drug resistance and identify the miR-140-5p/miR-28-3p/SPRED1/MAPK pathway as a potential targetable axis for treating multiple myeloma.Hypoxia induces stromal cells to secrete extracellular vesicles with increased miR-140-5p and miR-28-3p that are transferred to multiple myeloma cells and drive drug resistance by increasing the MAPK signaling.
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