期刊
CANCER RESEARCH
卷 81, 期 9, 页码 2386-2398出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-3453
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资金
- Strategic Priority Research Program of CAS [XDB29040102, XDB37030206]
- National Natural Science Foundation of China [81672464, 31600723, 81988101, 81872231, 82073411]
- NIH NCI KL2 Career Development Award [KL2-TR-002385]
The study identifies a HBV-induced IL8/CXCR1/TGF beta signaling cascade that suppresses antitumor immunity and enhances metastasis in HCC. This provides new potential targets for therapeutic intervention.
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 IL8 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 IL8-CXCR1 cascade by overexpression of IL8 in tumor cells dramatically enhanced liver metastasis. Mechanistically, IL8 selectively induced GARP-latent-TGF beta 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 IL8-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. Significance: This study identifies a hepatitis B-induced IL8/CXCR1/TGF beta signaling cascade that suppresses antitumor immunity and enhances metastasis in hepatocellular carcinoma, providing new potential targets for therapeutic intervention.
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