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miR-221-5p and miR-186-5p Are the Critical Bladder Cancer Derived Exosomal miRNAs in Natural Killer Cell Dysfunction
Ting Huyan1, Lina Gao1, Na Gao1
1School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China.
Abstract:
Bladder cancer (BC) is the tenth most commonly diagnosed cancer worldwide, and its carcinogenesis mechanism has not been fully elucidated. BC is able to induce natural killer (NK) cell dysfunction and escape immune surveillance. The present study found that exosomes derived from the urinary bladder cancer cell line (T24 cell) contribute in generating NK cell dysfunction by impairing viability, and inhibiting the cytotoxicity of the NK cell on target cells. Meanwhile, T24 cell-derived exosomes inhibited the expression of the important functional receptors NKG2D, NKp30, and CD226 on NK cells as well as the secretion of perforin and granzyme-B. The critical miRNAs with high expression in T24 cell-derived exosomes were identified using high-throughput sequencing. Furthermore, following dual-luciferase reporter assay and transfection experiments, miR-221-5p and miR-186-5p were confirmed as interfering with the stability of the mRNAs of DAP10, CD96, and the perforin gene in NK cells and may be potential targets used in the therapy for BC.
Insights
Bladder cancer exosomes impair natural killer (NK) cell function, hindering immune response. Specific microRNAs within these exosomes may offer novel therapeutic targets for bladder cancer treatment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Bladder cancer (BC) is a prevalent malignancy with incompletely understood carcinogenesis.
- BC can evade immune surveillance by inducing natural killer (NK) cell dysfunction.
Purpose of the Study:
- To investigate the role of T24 cell-derived exosomes in NK cell dysfunction.
- To identify microRNAs (miRNAs) in these exosomes that mediate NK cell inhibition and explore their therapeutic potential.
Main Methods:
- Characterization of T24 cell-derived exosomes and their effects on NK cell viability and cytotoxicity.
- Analysis of functional receptor expression (NKG2D, NKp30, CD226) and cytotoxic molecule secretion (perforin, granzyme-B) in NK cells.
- High-throughput sequencing to identify exosomal miRNAs, followed by dual-luciferase reporter assays and transfection experiments to validate miRNA targets (DAP10, CD96, perforin).
Main Results:
- T24 cell-derived exosomes impaired NK cell viability and cytotoxicity.
- Exosomes reduced the expression of NKG2D, NKp30, and CD226 on NK cells and inhibited perforin and granzyme-B secretion.
- miR-221-5p and miR-186-5p were identified as key miRNAs in T24 exosomes, targeting DAP10, CD96, and perforin mRNA.
Conclusions:
- Exosomes from bladder cancer cells induce NK cell dysfunction.
- Specific miRNAs (miR-221-5p, miR-186-5p) within these exosomes represent potential therapeutic targets for bladder cancer.
