Sirtuin2 enhances the tumoricidal function of liver natural killer cells in a mouse hepatocellular carcinoma model
Sirtuin2 enhances the tumoricidal function of liver natural killer cells in a mouse hepatocellular carcinoma model
复制标题
DOI：
10.1007/s00262-019-02337-5
复制
发表时间：
2019-06-01
影响因子：
5.8
通讯作者：
Zhou, Feng
中科院分区：
文献类型：
--
作者：
Chen, Ming;Xu, Min;Zhou, Feng
肝细胞癌（HCC）是世界上第三大致死性癌症。自然杀伤（NK）细胞介导的免疫对于肿瘤监测和治疗至关重要。NK细胞功能调控机制的表征对于开发针对HCC的新型免疫疗法是重要的。在这项研究中，我们使用化学诱导的小鼠HCC模型来鉴定肝脏NK细胞中Sirtuin 2（SIRT 2）的上调。特别是，SIRT 2主要在肝脏CD 94（+）NK细胞中表达。HCC肝脏微环境诱导NK细胞中SIRT 2的表达。此外，外源性SIRT 2的过表达显著上调了活化NK细胞中细胞因子和细胞毒性介质的产生。结论：SIRT 2过表达的NK细胞对肝癌细胞具有较强的杀伤作用。此外，SIRT 2显著促进活化的NK细胞中的细胞外信号调节激酶1/2（Erk 1/2）和p38丝裂原活化蛋白激酶（MAPK）的磷酸化。肝脏CD 94（+）NK细胞中SIRT 2的敲低削弱了它们对肝癌细胞的细胞毒性作用。我们的研究表明，SIRT 2增强肝癌中肝脏NK细胞的杀瘤活性。
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.