Hypoxic Bone Marrow Stromal Cells Secrete miR-140–5p and miR-28–3p That Target SPRED1 to Confer Drug Resistance in Multiple Myeloma
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Abstract
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. Significance: 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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RNA sequencing indicated increased levels of miR-140-5p and miR-28-3p in hypoxic bone marrow stromal cell-derived small extracellular vesicles, which imparted bortezomib resistance in multiple myeloma cells through targeting of SPRED1, a regulator of MAPK activation.
“RNA sequencing indicated increased levels of miR-140-5p and miR-28-3p in hypoxic BMSC-derived sEVs, which imparted bortezomib resistance in multiple myeloma cells through the targeting of SPRED1, a regulator of MAPK activation.”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [238]
Hypoxia enhances the release of small extracellular vesicles from bone marrow stromal cells.
“Research by Zhang et al. [238]. demonstrated that hypoxia enhances the release of small extracellular vesicles (sEVs) from bone marrow stromal cells (BMSCs).”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [238]
Small extracellular vesicles exhibited a greater attenuation of bortezomib sensitivity in multiple myeloma cells compared to those derived from bone marrow stromal cells under normoxic conditions.
“Small extracellular vesicles (sEVs) exhibited a greater attenuation of bortezomib sensitivity in multiple myeloma cells compared to those derived from bone marrow stromal cells (BMSCs) under normoxic conditions.”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [238]
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- Authors
- Zhang, H., Du, Z., Tu, C., Zhou, X., Menu, E., & Wang, J.
- Affiliations
- Guangzhou Medical University Cancer Hospital (CN)
- Vrije Universiteit Brussel (BE)
- Corresponding author
- Wang, Jinheng
- Venue
- Cancer Research
- Published
- 2023-09-26
- Volume
- 84
- Issue
- 1
- Pages
- 39-55
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W4387089916
- Cited by
- 17
- References
- 76
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 5
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- green
- biblio.vub.ac.be
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Basic and applied basic research foundation of Guangzhou municipality (202102020428, 202201011861)
- Tertiary Education Scientific research project of Guangzhou Municipal Education Bureau (202235397)
- Key Discipline of Guangzhou Education Bureau (201851839)
- National Natural Science Foundation of China (82100224)
- Basic and Applied Basic Research Foundation of Guangdong Province (2019A1515011126)
- key project of provincial basic and applied basic research of Guangdong general colleges and university (2019KZDXM041)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- multiple myeloma, mesenchymal stem cells, hypoxia, small extracellular vesicles, miR-140-5p, miR-28-3p, SPRED1, bortezomib resistance, MAPK signaling, drug resistance, tumor microenvironment, microRNA transfer
- MeSH terms
- Extracellular Vesicles, Bortezomib, Animals, Hypoxia, Multiple Myeloma, Drug Resistance, Neoplasm, MicroRNAs, Mice, Tumor Microenvironment, Mesenchymal Stem Cells
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