乙肝阳性肝癌活化CXCL8/CXCR1促使肿瘤血管转移的功能机制研究

Hepatitis B virus (HBV) infection is the major cause of liver cancer in China. Especially, HBV infection was involved in the presence of immune-edited environment in HBV-related HCC to promote vascular metastasis, such as portal vein tumor thrombosis (Yang et al, Cancer Cell, 2012). Following our initial analyses on the expression profiles of cytokines and chemokines that changed with metastatic potential of HCC cells, we have identified CXCL8 cytokines/chemokines as candidates for further in-depth investigations to elucidate their roles in HCC progression and vascular metastasis, potentially through its receptor CXCR1 in vascular endothelial cells altering the pathological nature of tumor microenvironment. To test this hypothesis, we explored a human CXCR1 transgenic mouse and intrasplenic plant CXCL8-Hepa1-6 HCC cells, in which we surprisingly found almost 100% lung metastasis in this mouse model. Based on these exciting progress, we aims to firstly investigate the upstream of CXCL8 signaling among the clinical samples as well as cellular HBV infection platform. Mechanistically, we will explore several systemic technology including endothelium-specific transgene, and lenti-viral sytem, to investigate essential mechanism of CXCL8/CXCR1 in mediating vascular inflammation, tumor cell adhesion with endothelial and changing endothelial permeability. Our study aims to provide new animal model, new signal pathways and new therapeutic drug target for HBV-related HCC vascular metastasis.

乙肝病毒（HBV）感染是我国肝癌发病的主要病因，研究表明HBV与肝癌患者门静脉癌栓等血管转移密切相关（Yang et al, Cancer Cell, 2012）。前期研究从HBV阳性肝癌中细胞/趋化因子筛查入手，发现HBV 阳性肝癌细胞高表达CXCL8，提示通过其受体CXCR1参与肿瘤血管转移。我们在脾脏接种CXCL8-Hepa1-6肝癌细胞的hCXCR1内皮转基因小鼠中检测到稳定继发性肺转移和初步门静脉病变。在此基础上，我们将首先从上游明确HBV阳性肝癌临床病理和细胞感染过程中CXCL8/CXCR1信号的活化机制；在整体和细胞水平观测该信号参与血管炎症、肿瘤与血管粘附、癌细胞促血管通透等病理作用环节；找到CXCL8/CXCR1促进血管转移的靶向信号和分子，从癌/血管内皮间相互作用中找到促进肿瘤转移的分子机制。本研究有望为肝癌血管转移的防治提供新的小鼠模型、信号机制和新型的治疗靶标。

乙肝病毒（HBV）感染是我国肝癌发病的主要病因，前期研究表明HBV与肝癌患者门静脉癌栓等血管转移密切相关。项目研究发现，HBV感染可通过HBx蛋白表达激活MEK-ERK等信号通路上调IL-8的表达，与肝癌血管转移相关。体外功能机制实验研究表明IL8-CXCR1信号轴可通过上调多个金属蛋白酶表达增强血管内皮的通透性；体内荷瘤实验发现，IL8-CXCR1信号轴可以促进肿瘤的肝转移和肝原位肿瘤生长，而不影响肿瘤的肺转移。通过分析免疫微环境组分，发现Treg细胞在Cdh5-Cre-hCXCR1小鼠肝脏中特异的增多。进一步研究发现，CXCR1可以和肝血窦内皮GARP相互作用并上调其表达，进而上调latent TGF-β的表达并增强肝血窦内皮细胞诱导Treg细胞的免疫抑制能力，促进肿瘤免疫逃逸和肝内血管转移。本研究阐释了HBV感染上调IL8-CXCR1信号轴并促进肝癌血管浸润转移的机制，有望为肝癌血管转移提供新的治疗靶点和思路。项目研究围绕HBV炎性微环境对肝癌发展及血管转移的调节机制这一核心科学问题，发现HBV与宿主互作，及HDAC6、Nogo-B、CCL22-CCR4和METTL3等多个参与调控炎-癌转化及病毒与肿瘤免疫逃逸的关键分子,为HBV感染及相关疾病的诊疗提供了多个潜在靶点和研究方向。项目执行期间，在Hepatology、Nature Communications、Cell Discovery、Pharmacological Research杂志发表基金标注论文5篇，应邀在Pharmacological Research杂志撰写综述，另有两篇论文分别被Cancer Research和Nature Communications杂志刚接受，均为最后通讯作者，顺利完成项目研究计划。