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In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells
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miR-335-laden B Cell-Derived Extracellular Vesicles Promote SOX4-Dependent Apoptosis in Human Multiple Myeloma Cells
Elisabetta Lombardi1, Gonzalo Almanza2, Kinga Kowal1,3
1Stem Cell Unit, Department of Research and Advance Cancer Diagnostic, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
Abstract:
Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow. Despite novel therapies, MM still remains an incurable cancer and new strategies are needed. Increased expression of the transcription factor Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4) has been correlated with tumor development and progression through a variety of distinct processes, including inhibition of apoptosis, increased cell invasion and metastasis, and induction and maintenance of cancer-initiating cells. The role of SOX4 in MM is largely unknown. Since SOX4 is a known target of miR-335, we used miR-335 to assess whether SOX4 modulation could promote apoptosis in MM cells. Using an MM cell model we show that miR-335 acts both on SOX4-related genes (AKT, PI3K) and hypoxia-inducible factor 1-alpha (Hif1-α). In addition, we show miR-335-laden extracellular vesicles induced in B cells (iEVs) are also effective in targeting SOX4, causing apoptosis. Collectively, we propose that miR-335-laden iEVs could be developed as a novel form of gene therapy in MM.
Insights
This study explores targeting Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4) in multiple myeloma (MM) using miR-335. miR-335-loaded extracellular vesicles show potential for novel gene therapy in MM.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Multiple myeloma (MM) is a fatal plasma cell cancer with limited treatment options.
- SOX4 (Sex-determining region Y-related high-mobility-group box transcription factor 4) is implicated in various cancers but its role in MM is unclear.
- SOX4 is a known target of miR-335, suggesting a potential therapeutic link.
Purpose of the Study:
- To investigate the role of SOX4 in MM.
- To determine if miR-335 can modulate SOX4 expression and induce apoptosis in MM cells.
- To evaluate the therapeutic potential of miR-335-laden extracellular vesicles (iEVs) in MM.
Main Methods:
- Utilized an MM cell model to study miR-335 effects.
- Analyzed the impact of miR-335 on SOX4-related genes (AKT, PI3K) and hypoxia-inducible factor 1-alpha (Hif1-α).
- Assessed the efficacy of miR-335-laden iEVs derived from B cells in targeting SOX4 and inducing apoptosis.
Main Results:
- miR-335 was shown to target SOX4-related genes (AKT, PI3K) and Hif1-α in MM cells.
- miR-335-laden iEVs effectively targeted SOX4 in MM cells, leading to apoptosis.
- SOX4 modulation by miR-335 demonstrated anti-cancer effects in the MM cell model.
Conclusions:
- miR-335 plays a role in regulating key pathways involved in MM progression.
- miR-335-laden iEVs represent a promising novel gene therapy strategy for multiple myeloma.
- Targeting SOX4 via miR-335 offers a potential new avenue for MM treatment.
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