Elevated neutrophil extracellular traps by HBV-mediated S100A9-TLR4/RAGE-ROS cascade facilitate the growth and metastasis of hepatocellular carcinoma  

作　　者：Xi Zhan RuiWu Xue-Hua Kong Yan You Kun He Xiao-Yu Sun Yong Huang Wei-Xian Chen Liang Duan 

机构地区：[1]Department of Laboratory Medicine,The Second Affiliated Hospital of Chongqing Medical University,Chongqing 400000,P.R.China [2]Department of Laboratory Medicine,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,P.R.China [3]Key Laboratory of Laboratory Medical Diagnostics,Ministry of Education,Department of Laboratory Medicine,Chongqing Medical University,Chongqing 400010,P.R.China [4]Department of Pathology,The Second Affiliated Hospital of Chongqing Medical University,Chongqing 400000,P.R.China [5]Department of Hepatobiliary Surgery,The Second Affiliated Hospital of Chongqing Medical University,Chongqing 400000,P.R.China

出　　处：《Cancer Communications》2023年第2期225-245,共21页癌症通讯（英文）

基　　金：the National Natural Science Foundation of China(82072364 and 82002152);the Chongqing medical scientific research project(Joint project of Chongqing Health Commission and Science and Technology Bureau,2020FYYX038);Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University and Senior Medical Talents Programof Chongqing for Young and Middle-aged(2022-15).

摘　　要：Background:Neutrophil extracellular traps(NETs)are considered significant contributors to cancer progression,especially metastasis.However,it is still unclear whether NETs are involved in hepatitis B virus(HBV)-related hepatocarcinogenesis and have potential clinical significance during evaluation and management for hepatocellular carcinoma(HCC).In this study,we aimed to investigate the functional mechanism of NETs in HBV-related hepatocarcinogenesis and their clinical significance.Methods:A total of 175 HCC patients with and without HBV infection and 58 healthy controls were enrolled in this study.NETs weremeasured in tissue specimens,freshly isolated neutrophils and blood serum from these patients,and the correlation of circulating serum NETs levels with malignancy was evaluated.The mechanism by which HBV modulates NETs formation was explored using cell-based studies.In addition,in vitro and in vivo experiments were further performed to clarify the functional mechanism of NETs on the growth and metastasis of HCC.Results:We observed an elevated level of NETs in blood serum and tissue specimens from HCC patients,especially those infected with HBV.NETs facilitated the growth and metastasis of HCC both in vitro and in vivo,which were mainly dominated by increased angiogenesis,epithelial-mesenchymal transition(EMT)-related cell migration,matrix metalloproteinases(MMPs)-induced extracellular matrix(ECM)degradation and NETs-mediated cell trapping.Inhibition of NETs generation by DNase 1 effectively abrogated the NETs-aroused HCC growth and metastasis.In addition,HBV-induced S100A9 accelerated the generation of NETs,which was mediated by activation of toll-like receptor(TLR4)/receptor for advanced glycation end products(RAGE)-reactive oxygen species(ROS)signaling.Further,circulatory NETs were found to correlate with viral load,TNM stage and metastasis status in HBV-related HCC,and the identified NETs could predict extrahepatic metastasis,with an area under the ROC curve(AUC)of 0.83 and 90.3%sensitivity and 62.8%specifi

关 键 词：hepatocellular carcinoma hepatitis B virus METASTASIS neutrophil extracellular trap RAGE ROS S100A9 TLR4 

分 类 号：R735.7[医药卫生—肿瘤]