Cancer Research, 2 March, 2021, DOI：https://doi.org/10.1158/0008-5472.CAN-20-3453
Hepatitis B-induced IL-8 Promotes Hepatocellular Carcinoma Venous Metastasis and Intrahepatic Treg Accumulation
Changlu Zhang, Yanan Gao, Chengzhi Du, Geoffrey J. Markowitz, Jing Fu, Zhenxing Zhang, Chunliang Liu, Wenhao Qin, Hongyang Wang, Fan Wang, and Pengyuan Yang
Hepatitis B-associated hepatocellular carcinoma (HCC) is often accompanied by severe vascular invasion and portal vein tumor thrombus leading to a poor prognosis. However, the underlying mechanism of this disease remains obscure. In this study, we demonstrate that the hepatitis B virus (HBV)-encoded gene HBx induces high IL-8 production through MEK-ERK signal activation, leading to enhanced endothelial permeability to facilitate tumor vascular invasion. In a vascular metastatic model using a tail vein injection in a transgenic mouse with selective expression of human CXCR1 in the endothelium, activation of the IL-8-CXCR1 cascade by overexpression of IL-8 in tumor cells dramatically enhanced liver metastasis. Mechanistically, IL-8 selectively induced GARP-latent-TGF-β in liver sinusoidal endothelial cells and subsequently provoked preferential regulatory T cell polarization to suppress antitumor immunity. Collectively, these findings reveal a hepatitis B-associated IL-8-CXCR1 signaling axis that mediates vascular invasion and local microenvironmental immune escape of HCC to induce intrahepatic metastasis, which may serve as potential therapeutic targets for HBV-associated HCC.