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Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
MicroRNA-150 regulates the cytotoxicity of natural killers by targeting perforin-1
Nayoung Kim1, Miju Kim2, Sohyun Yun1
1Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
Background:
Perforin-1 (Prf1) is the predominant cytolytic protein secreted by natural killer (NK) cells. For a rapid immune response, resting NK cells contain high Prf1 mRNA concentrations while exhibiting minimal cytotoxicity caused by a blockage of Prf1 protein synthesis, implying that an unknown posttranscriptional regulatory mechanism exists.
Objective:
We sought to determine whether microRNA-150 (miR-150) posttranscriptionally regulates Prf1 translation in both mouse and human NK cells at rest and at various time points after activation.
Methods:
Mouse NK cells with a targeted deletion of miR-150 (miR-150(-/-) NK cells), primary human NK cells, and NK92 MI cells were used to investigate the role of miR-150 in NK cells. NK cell cytotoxicity assays and Western blotting proved that activated miR-150(-/-) NK cells expressed upregulated Prf1, augmenting NK cell cytotoxicity. When immunodeficient mice were injected with miR-150(-/-) NK cells, there was a significant reduction in tumor growth and metastasis of B16F10 melanoma.
Results:
We report that miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. Mouse wild-type NK cells displayed downregulated miR-150 expression in response to IL-15, which led to corresponding repression and induction of Prf1 during rest and after IL-15 activation, respectively.
Conclusion:
Our results indicate that miR-150 is a common posttranscriptional regulator for Prf1 in mouse and human NK cells that represses NK cell lytic activity. Thus the therapeutic control of miR-150 in NK cells could enhance NK cell-based immunotherapy against cancer, providing a better clinical outcome.
Insights
MicroRNA-150 (miR-150) represses natural killer (NK) cell cytotoxicity by downregulating perforin-1 (Prf1) expression. Inhibiting miR-150 enhances NK cell anti-cancer activity, offering a potential immunotherapy strategy.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Natural killer (NK) cells are crucial for rapid immune responses, utilizing perforin-1 (Prf1) for cytotoxicity.
- Resting NK cells have high Prf1 mRNA but low cytotoxicity, suggesting posttranscriptional regulation.
- The specific mechanism controlling Prf1 synthesis in resting NK cells remained elusive.
Purpose of the Study:
- To investigate the role of microRNA-150 (miR-150) in the posttranscriptional regulation of Prf1.
- To determine if miR-150 affects Prf1 translation in both mouse and human NK cells.
- To assess the impact of miR-150 on NK cell function at rest and after activation.
Main Methods:
- Utilized miR-150 knockout mouse NK cells, primary human NK cells, and NK92 MI cells.
- Performed NK cell cytotoxicity assays and Western blotting to evaluate Prf1 levels and function.
- Assessed the effect of miR-150 deletion on tumor growth and metastasis in immunodeficient mice.
Main Results:
- miR-150 directly binds to the 3' untranslated regions of Prf1 mRNA in both mouse and human cells.
- miR-150 downregulates Prf1 expression, thereby repressing NK cell cytotoxic activity.
- IL-15 activation downregulated miR-150, leading to increased Prf1 expression and enhanced NK cell cytotoxicity.
- NK cells lacking miR-150 exhibited augmented cytotoxicity and reduced tumor growth in vivo.
Conclusions:
- miR-150 acts as a key posttranscriptional regulator of Prf1 in NK cells.
- miR-150 represses NK cell lytic function, impacting anti-tumor immunity.
- Targeting miR-150 in NK cells presents a promising strategy for enhancing cancer immunotherapy and improving clinical outcomes.
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