Dual role of ANGPTL8 in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis
Yujiu Gao,
Yue Yuan,
Shu Wen,
Yanghui Chen,
Zongli Zhang,
Ying Feng,
Bin Jiang,
Shinan Ma,
Rong Hu,
Chen Fang,
Xuzhi Ruan,
Yahong Yuan,
Xinggang Fang,
Chao Luo,
Zhongji Meng,
Xiaoli Wang,
Xingrong Guo
Affiliations
Yujiu Gao
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Yue Yuan
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Shu Wen
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Yanghui Chen
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Zongli Zhang
Institute of Pediatric Disease, Taihe Hospital
Ying Feng
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Bin Jiang
Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital
Shinan Ma
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Rong Hu
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Chen Fang
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Xuzhi Ruan
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Yahong Yuan
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Xinggang Fang
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Chao Luo
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Zhongji Meng
Department of Infectious Diseases, Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital
Xiaoli Wang
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Xingrong Guo
Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine
Abstract The interplay between hepatocellular carcinoma (HCC) cells and the tumor microenvironment is essential for hepatocarcinogenesis, but their contributions to HCC development are incompletely understood. We assessed the role of ANGPTL8, a protein secreted by HCC cells, in hepatocarcinogenesis and the mechanisms through which ANGPTL8 mediates crosstalk between HCC cells and tumor-associated macrophages. Immunohistochemical, Western blotting, RNA-Seq, and flow cytometry analyses of ANGPTL8 were performed. A series of in vitro and in vivo experiments were conducted to reveal the role of ANGPTL8 in the progression of HCC. ANGPTL8 expression was positively correlated with tumor malignancy in HCC, and high ANGPTL8 expression was associated with poor overall survival (OS) and disease-free survival (DFS). ANGPTL8 promoted HCC cell proliferation in vitro and in vivo, and ANGPTL8 KO inhibited the development of HCC in both DEN-induced and DEN-plus-CCL4-induced mouse HCC tumors. Mechanistically, the ANGPTL8–LILRB2/PIRB interaction promoted polarization of macrophages to the immunosuppressive M2 phenotype in macrophages and recruited immunosuppressive T cells. In hepatocytes, ANGPTL8-mediated stimulation of LILRB2/PIRB regulated the ROS/ERK pathway and upregulated autophagy, leading to the proliferation of HCC cells. Our data support the notion that ANGPTL8 has a dual role in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis.