Berberine enhances the anti-hepatocellular carcinoma effect of NK92-MI cells through inhibiting IFN-gamma-mediated PD-L1 expression  

作　　者：Kunyuan Wang Chengxin Gu Ganxiang Yu Jiaen Lin Zhilei Wang Qianting Lu Yangzhi Xu Dan Zhao Xiaofeng Jiang Weijian Mai Shiming Liu Hui Yang 

机构地区：[1]Department of Gastroenterology,The Second Affiliated Hospital of Guangzhou Medical University,Guangzhou,Guangdong,China [2]Department of Hepatobiliary Surgery,The Second Affiliated Hospital of Guangzhou Medical University,Guangzhou,Guangdong,China [3]Guangzhou Institute of Cardiovascular Disease,The Second Affiliated Hospital of Guangzhou Medical University,Guangzhou,Guangdong,China

出　　处：《Liver Research》2022年第3期167-174,共8页肝脏研究（英文）

基　　金：This study was supported by grants from the General Project of Guangdong Natural Science Foundation(2021A1515010795,2020A1515011255)to H.Yang;the National Natural Science Foundation of China(no.81372634)to H.Yang;the Medical Science and Technology Research Foundation of Guangdong Province(B2020114)to C.Gu;the Guangzhou Health Science and Technology Project(20201A010054)to C.Gu.

摘　　要：Background and aims:Berberine is one of the most promising clinically tested natural alkaloids,and immunotherapy using natural killer(NK)cells is a potentially effective treatment for hepatocellular carcinoma(HCC).This study aims to elucidate the effect of berberine on the anti-HCC effect of NK92-MI cells.Materials and methods:Human HCC SMMC-7721 and Hep3B cells were co-incubated with NK92-MI cells,berberine(60 or 80 mmol/L),or their combination for 36 h.To evaluate the killing effect of NK92-MI cells on HCC cells,the release of lactate dehydrogenase(LDH)in HCC cells was measured.The anti-tumor effects of berberine,NK92-MI cells,and their combinations were evaluated by MTS,EdU,Tunel,and Western blot assays.A male BALB/c nude mouse subcutaneous tumor model was used to investigate the anti-HCC effect of berberine and NK92-MI cells in vivo.Results:The LDH assay showed that berberine enhanced the cytotoxicity of NK92-MI cells on HCC cells.The combination of berberine and NK92-MI cells demonstrated more obvious anti-HCC effect than did the berberine or NK92-MI single treatment in inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo.Mechanistically,the expression of programmed cell death-ligand 1(PD-L1)in HCC cells was upregulated after co-culture with NK-92MI cells.PD-L1 expression was knocked down,thereby inhibiting the proliferation and promoting apoptosis of HCC cells,and inhibited by berberine that blocked the secretion of interferon gamma(IFN-g),thereby enhancing the anti-tumor effect of NK92-MI cells.Conclusions:Current data show that the immunomodulatory role of berberine is to enhance the cytotoxic effect of NK92-MI cells and inhibit tumor immune escape by reducing the expression of PD-L1.Our study provides a rationale for the clinical application of berberine in combination with NK cells for the treatment of HCC.

关 键 词：BERBERINE Hepatocellular carcinoma(HCC) NK92-MI cells Interferon gamma(IFN-g) Programmed cell death-ligand 1(PD-L1) 

分 类 号：R735.7[医药卫生—肿瘤]