Department of Blood Transfusion, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Hematology and Oncology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer Immunol Immunother. 2019 Jun;68(6):961-971. doi: 10.1007/s00262-019-02337-5. Epub 2019 Apr 6.
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.
肝细胞癌 (HCC) 是全球第三大致命癌症。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 细胞功能的调控机制的特征对于开发针对 HCC 的新型免疫疗法很重要。在这项研究中，我们使用化学诱导的小鼠 HCC 模型来鉴定肝 NK 细胞中 Sirtuin2 (SIRT2) 的上调。特别是，SIRT2 在肝 CD94 NK 细胞中表达丰富。HCC 肝微环境诱导 NK 细胞中 SIRT2 的表达。此外，外源性 SIRT2 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。一致地，SIRT2 过表达的 NK 细胞对肝癌细胞表现出更强的杀伤作用。此外，SIRT2 显著促进了活化 NK 细胞中细胞外信号调节激酶 1/2 (Erk1/2) 和丝裂原活化蛋白激酶 (MAPK) 的磷酸化。肝 CD94 NK 细胞中的 SIRT2 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，SIRT2 增强了 HCC 中肝 NK 细胞的杀伤活性。
