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Updated: Apr 22, 2026
Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1
Tomohiro Umezu1, Hiroko Tadokoro2, Kenko Azuma3
1Department of Molecular Science, Tokyo Medical University, Tokyo, Japan; Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
Abstract:
Exosomes are small endosome-derived vesicles containing a wide range of functional proteins, mRNA, and miRNA. Exosomal miRNA from cancer cells helps modulate the microenvironment. In multiple myeloma (MM), the massive proliferation of malignant plasma cells causes hypoxia. To date, the majority of in vitro hypoxia studies of cancer cells have used acute hypoxic exposure (3-24 hours). Thus, we attempted to clarify the role of MM-derived exosomes in hypoxic bone marrow by using MM cells grown continuously in vitro under chronic hypoxia (hypoxia-resistant MM [HR-MM] cells). The HR-MM cells produced more exosomes than the parental cells under normoxia or acute hypoxia conditions, and miR-135b was significantly upregulated in exosomes from HR-MM cells. Exosomal miR-135b directly suppressed its target factor-inhibiting hypoxia-inducible factor 1 (FIH-1) in endothelial cells. Finally, exosomal miR-135b from HR-MM cells enhanced endothelial tube formation under hypoxia via the HIF-FIH signaling pathway. This in vitro HR myeloma cell model will be useful for investigating MM cell-endothelial cell interactions under hypoxic conditions, which may mimic the in vivo bone marrow microenvironment. Although tumor angiogenesis is regulated by various factors, exosomal miR-135b may be a target for controlling MM angiogenesis.
Insights
Multiple myeloma cells under chronic hypoxia release exosomes with miR-135b. This exosomal microRNA promotes blood vessel formation in endothelial cells, suggesting a new therapeutic target for multiple myeloma angiogenesis.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Exosomes are vesicles involved in intercellular communication, carrying functional molecules like miRNA.
- Cancer cells, including multiple myeloma (MM) cells, can alter their microenvironment via exosomal contents.
- Chronic hypoxia in the bone marrow is a hallmark of MM, yet its effects on exosome production and function are not fully understood.
Purpose of the Study:
- To investigate the role of exosomes derived from multiple myeloma cells cultured under chronic hypoxia.
- To determine the specific miRNA cargo and functional impact of these exosomes on endothelial cells.
- To establish a model for studying MM cell-endothelial cell interactions in a hypoxic bone marrow mimic.
Main Methods:
- Cultured multiple myeloma (MM) cells under chronic hypoxia to generate hypoxia-resistant MM (HR-MM) cells.
- Characterized exosome production and miRNA content from HR-MM cells compared to parental cells.
- Assessed the effect of exosomal miR-135b on endothelial cells, focusing on target gene suppression and tube formation.
- Utilized the HIF-FIH signaling pathway as a mechanistic link.
Main Results:
- HR-MM cells produced significantly more exosomes than parental cells.
- Exosomes from HR-MM cells showed significantly higher levels of miR-135b.
- Exosomal miR-135b suppressed its target, factor-inhibiting hypoxia-inducible factor 1 (FIH-1), in endothelial cells.
- Exosomal miR-135b enhanced endothelial tube formation under hypoxia via the HIF-FIH pathway.
Conclusions:
- Chronic hypoxia induces increased exosome production with elevated miR-135b in multiple myeloma cells.
- Exosomal miR-135b plays a crucial role in promoting angiogenesis in the MM microenvironment by targeting FIH-1.
- This study provides a valuable in vitro model for MM-endothelial cell interactions and identifies exosomal miR-135b as a potential therapeutic target for controlling MM angiogenesis.
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