Sirtuin2 enhances the tumoricidal function of liver natural killer cells in a mouse hepatocellular carcinoma model
Hepatocellular carcinoma (HCC) is the third most lethal cancer in the world. Natural killer (NK) cell-mediated immunity is crucial for tumor surveillance and therapy. Characterization of the regulatory mechanisms of NK cell function is important for developing novel immunotherapies against HCC. In this study, we used a chemical-induced mouse HCC model to identify the upregulation of Sirtuin2 (SIRT2) in liver NK cells. In particular, SIRT2 was predominantly expressed in liver CD94+ NK cells. The HCC liver microenvironment induced SIRT2 expression in NK cells. In addition, overexpression of exogenous SIRT2 significantly upregulated the production of cytokines and cytotoxic mediators in activated NK cells. Consistently, SIRT2-overexpressing NK cells showed a stronger tumoricidal effect on hepatoma cells. Moreover, SIRT2 remarkably promoted the phosphorylation of Extracellular-signal-regulated kinase 1/2 (Erk1/2) and p38 Mitogen-activated protein kinases (MAPK) in activated NK cells. SIRT2 knockdown in liver CD94+ NK cells impaired their cytotoxic effect on hepatoma cells. Our study indicates that SIRT2 enhances the tumoricidal activity of liver NK cells in HCC.
KeywordsSirtuin2 NK cells Erk1/2 p38 Hepatocellular carcinoma
Glyceraldehyde 3-phosphate dehydrogenase
Green fluorescent protein
Jun N-terminal kinase
Mitogen-activated protein kinases
Multiplicity of infection
Nicotinamide adenine dinucleotide
- NK cells
Natural killer cells
Natural killer group 2
MC conducted the animal model, cell sorting, quantitative RT-PCR, adoptive transfer, and in vitro culture. MX prepared the lentiviruses and performed the lentiviral transduction. CZ conducted the immunoblotting analysis. HW did the intracellular staining and flow cytometry analysis. QZ conducted the statistical analysis. FZ designed the experiments, analyzed the data and composed the manuscript.
This study was supported by the National Natural Science Foundation of China (Grant No. 81470823) and the Natural Science Foundation of Hubei Province (Grant No. 2013CFB304).
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflict of interest.
The animal study was approved by the Wuhan University Animal Care and Use Committee (animal research approval number: 11400700245566). The animal experiments were performed following the Wuhan University Animal Use Guidelines.
Not applicable because no human subjects were included.
All mice were obtained from SBS Genetech Co, Ltd.
Cell line authentication
Not applicable because primary NK cells were used. The mouse hepatoma cell line Hepa1-6RAE1 was a gift from another lab (from Dr. Kai Dai, Wuhan University) so no authentication information was gained. The HEK293T cell line was purchased from Procell Life Science & Technology Co, Ltd. (Wuhan, China) and was not authenticated, because this cell line was only used for lentivirus packaging in the current study.
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