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MiR-30c facilitates natural killer cell cytotoxicity to lung cancer through targeting GALNT7

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Abstract

Background

MicroRNAs (miRNAs) have been reported to play important roles in regulating natural killer (NK) cell cytotoxicity to cancer cells.

Objective

This study aimed to investigate the effects and potential mechanism of miR-30c in regulating NK cell cytotoxicity to lung cancer cells.

Methods

Primary NK cells were derived from the peripheral blood of lung cancer and normal participants. Exosomes were isolated and validated via transmission electron microscopy and nanoparticle tracking analysis. The levels of miR-30c, polypeptide N-acetylgalactosaminyltransferase 7 (GALNT7) and proteins in PI3K/AKT pathway were determined using quantitative real-time polymerase chain reaction or western blot. Tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) levels and the cytotoxicity of effector NK cells to target lung cancer cells were measured via enzyme linked immunosorbent assay, cell apoptosis or xenograft experiments. The relationship between miR-30c and GALNT7 was analyzed by luciferase activity, RNA pull-down and RNA immunoprecipitation assays. And a xenograft mice model was established to verify the effect of miR-30c in regulating NK cell cytotoxicity to lung cancer cells in vivo.

Results

NK cell-derived exosomes carrying miR-30c, and miR-30c level was significantly downregulated in primary NK cells of lung cancer patients. MiR-30c overexpression promoted TNF-α and IFN-γ secretion and enhanced the cytotoxicity of interleukin 2 (IL-2)-treated NK cells to lung cancer cells, while knockdown of miR-30c played an opposite effect in regulating the cytotoxicity of NK cells to lung cancer cells. GALNT7 was a target of miR-30c and was negatively regulated by miR-30c. Besides, miR-30c targeted GALNT7 to exert its function in regulating NK cell cytotoxicity. Furthermore, GALNT7 prompted the activation of PI3K/AKT pathway in NK cells. Additionally, miR-30c overexpression enhanced NK cell cytotoxicity to lung cancer cells and inhibited tumor growth in vivo.

Conclusion

miR-30c enhanced NK cell cytotoxicity to lung cancer cells via decreasing GALNT7 and inactivating the PI3K/AKT pathway, suggesting that regulating miR-30c expression maybe a promising approach for enhancing NK cell-based antitumor therapies.

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Abbreviations

miRNAs:

MicroRNAs

NK:

Natural killer

GALNT7:

N-acetylgalactosaminyltransferase 7

TNF-α:

Tumor necrosis factor-α

IFN-γ:

Interferon-γ

IL-2:

Interleukin 2

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Author notes

  1. Fei Gao and Jianjun Han contribute to this work equally as co-first authors.

Authors and Affiliations

  1. Department of Oncology, The Third Hospital of Mianyang, Sichuan Mental Health Center), No. 190, East Section of Jiannan Road, Sichuan, 621000, China

    Fei Gao, Jianjun Han, Li Jia, Jun He, Yun Wang, Mi Chen, Xiaojun Liu & Xia He

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  1. Fei Gao
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Contributions

Fei Gao,Jianjun Han design and research the experiment procedure, write the revision and article, Li Jia, Jun He, Yun Wang, Mi Chen, Xiaojun Liu and Xia He conduct experiments and collect data, and prepare for the preliminary survey, corresponding to Jianjun Han.

Corresponding author

Correspondence to Jianjun Han.

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Conflict of interest

Author Fei Gao, Author Jianjun Han,Author Li Jia, Author Jun He, Author Yun Wang, Author Mi Chen, Author Xiaojun Liu and Author Xia He declare that they have no conflicts of interests.

Declaration of Helsinki

All clinical experiments that include human blood samples or animal experiments were approved by the Ethics Committee of The Third Hospital of Mianyang. All procedures and protocols were performed according to the Declaration of Helsinki. The written consent of participants included in the study was obtained.

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Gao, F., Han, J., Jia, L. et al. MiR-30c facilitates natural killer cell cytotoxicity to lung cancer through targeting GALNT7. Genes Genom 45, 247–260 (2023). https://doi.org/10.1007/s13258-022-01306-0

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