乙型肝炎诱导的IL-8促进肝细胞癌静脉转移和肝内Treg积累

StephenW

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
Add to Cart ($50)
DOI: 10.1158/0008-5472.CAN-20-3453

    ArticleFigures & DataInfo & Metrics
    PDF

Abstract

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.

    Received October 13, 2020.
    Revision received January 18, 2021.
    Accepted March 1, 2021.

    Copyright ©2021, American Association for Cancer Research.

StephenW

乙型肝炎诱导的IL-8促进肝细胞癌静脉转移和肝内Treg积累
张长鹿，高亚男，杜成志，Geoffrey J.Markowitz，傅静，张振兴，刘春亮，秦文豪，王宏阳，王凡和杨鹏远
加入购物车（$ 50）
DOI：10.1158 / 0008-5472.CAN-20-3453

    文章图形与数据信息与度量
    PDF格式

抽象的

乙型肝炎相关的肝细胞癌（HCC）通常伴有严重的血管浸润和门静脉肿瘤血栓，导致不良预后。但是，这种疾病的潜在机制仍然不清楚。在这项研究中，我们证明了乙型肝炎病毒（HBV）编码的基因HBx通过MEK-ERK信号激活诱导高IL-8产生，从而导致内皮通透性增强，从而促进肿瘤血管的侵袭。在使用尾静脉注射在内皮细胞中选择性表达人CXCR1的转基因小鼠中的血管转移模型中，通过在肿瘤细胞中过表达IL-8激活IL-8-CXCR1级联可大大增强肝转移。从机制上讲，IL-8在肝窦内皮细胞中选择性诱导GARP潜伏性TGF-β，随后引发优先调节性T细胞极化，以抑制抗肿瘤免疫力。总的来说，这些发现揭示了乙型肝炎相关的IL-8-CXCR1信号轴介导HCC的血管侵袭和局部微环境免疫逸出，从而诱导肝内转移，这可能成为HBV相关HCC的潜在治疗靶标。

    2020年10月13日收到。
    修订于2021年1月18日收到。
    2021年3月1日接受

    美国癌症研究协会版权所有©2021。