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.

肝细胞癌 (HCC) 细胞与肿瘤微环境之间的相互作用对于肝癌发生至关重要，但它们对 HCC 发展的贡献尚不完全清楚。我们评估了 ANGPTL8（一种由 HCC 细胞分泌的蛋白质）在肝癌发生中的作用以及 ANGPTL8 介导 HCC 细胞与肿瘤相关巨噬细胞之间串扰的机制。对 ANGPTL8 进行了免疫组织化学、蛋白质印迹、RNA-Seq 和流式细胞术分析。进行了一系列体外和体内实验以揭示 ANGPTL8 在 HCC 进展中的作用。ANGPTL8表达与 HCC 肿瘤恶性程度呈正相关，高ANGPTL8表达与较差的总生存期 (OS) 和无病生存期 (DFS) 相关。ANGPTL8 在体外和体内促进 HCC 细胞增殖，ANGPTL8 KO 在 DEN 诱导和 DEN-plus-CCL4 诱导的小鼠 HCC 肿瘤中抑制 HCC 的发展。从机制上讲，ANGPTL8–LILRB2/PIRB 相互作用促进巨噬细胞极化为巨噬细胞中的免疫抑制 M2 表型并募集免疫抑制 T 细胞。在肝细胞中，ANGPTL8 介导的 LILRB2/PIRB 刺激可调节 ROS/ERK 通路并上调自噬，从而导致 HCC 细胞增殖。我们的数据支持这样的观点，即 ANGPTL8 在肝癌发生过程中具有促进肿瘤细胞增殖和免疫逃逸的双重作用。