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The role of IL-17 signaling in alcohol-induced HCC

IL-17 信号在酒精诱导的 HCC 中的作用

基本信息

批准号：
10627853
负责人：
DAVID A. BRENNER
金额：
$ 46.45万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-06 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627853
关键词：
AFP gene Ablation Acceleration Acetylgalactosamine Address Alcoholic Liver Diseases Alcohols Antisense RNA Archives Attenuated Body mass index CCL2 gene Caspase Cells Cholesterol Chronic Hepatitis B Cirrhosis Collaborations Data Development Exocytosis Experimental Models Fatty Liver Fibrosis Gene Expression Genes Genetic Goals Hepatic Stellate Cell Hepatitis B Incidence Hepatitis B Virus Hepatitis C Hepatitis C virus Hepatitis Viruses Hepatocyte Human IL17 Signaling Pathway IL17 gene In Vitro Incidence Inflammation Injury Interleukin-6 Interleukins Knock-out Knockout Mice Liver Liver Fibrosis Macrophage Malignant Neoplasms Mediating Mediator Metabolic Mus Mutagenesis Myeloid Cells Obesity Epidemic Oligonucleotides Pathogenesis Patients Primary carcinoma of the liver cells Production Resected Role SP1 gene STAT3 gene Side Signal Pathway Signal Transduction Signaling Molecule Steatohepatitis System Testing Therapeutic Tissues Translating Up-Regulation chemokine exosome gain of function genetic approach hepatocyte injury in vivo inhibitor injured insight lipid biosynthesis liver injury loss of function mouse model mutant nonalcoholic steatohepatitis novel novel therapeutics overexpression response therapeutic evaluation therapeutic target tool transcriptome sequencing

项目摘要

ABSTRACT: Hepatocellular carcinoma (HCC) is caused by hepatitis virus HBV/HCV, non-alcoholic steatohepatitis (NASH), and alcoholic liver disease (ALD), which typically progress from liver fibrosis, to cirrhosis and cancer. Our preliminary data demonstrate that genetic deletion of IL-17 signaling in steatotic hepatocytes significantly attenuates the development of HCC in ALD-injured mice, suggesting that IL-17 signaling is a target for anti- HCC therapy. Our central hypothesis is that IL-17 signaling regulates chemokine production, de novo lipogenesis, and TNFRI expression/turnover in steatotic hepatocytes. IL-17 signaling promotes ALD- and NASH-induced HCC via activation of TNF/TNFRI-SREBP1/2-DHCR7-cholesterol synthesis, and suppression of ARTS-1/NUC2-dependent TNFRI exocytosis. The goal of the study is to characterize the mechanism by which IL-17A/IL-17RA signaling regulates responses in metabolically injured hepatocytes, and to compare the pathways of IL-17 signaling in the experimental models of ALD- and NASH. Strategy: Responses to IL-17 signaling will be compared side-by side in ALD- and NASH-injured WT and hepatocyte-specific IL-17RA knockout mice with HCC. We determine if IL-17 signaling is similarly activated in NASH- and ALD-injured hepatocytes. We determine if blocking of IL-17 signaling in steatotic hepatocytes is sufficient to suppress HCC in the metabolically injured liver. Specifically, the role of IL-17 in the pathogenesis of DEN- or (Mup-uPA)- induced HCC in ALD- and NASH-injury will be studied in WT and hepatocyte-specific IL-17RA knockout mice (IL-17RAΔHep mice). Development of HCC, inflammation, steatosis and liver fibrosis will be across all groups of mice. Mutagenesis of WT and IL-17RA-deficient AFP+YAP+ HCC, and responses of steatotic hepatocytes to IL-17A will be characterized. Specifically, we determine if chemokine secretion, cholesterol synthesis are suppressed in metabolically injured IL-17RA-deficient hepatocytes (AIM1). We will test a novel hypothesis by which IL-17 signaling facilitates TNF/TNFRI-Caspase2-SP1-SREBP1/2-DHCR7-dependent cholesterol synthesis in steatotic hepatocytes via blocking ARTS-1-NUCB2-regulated TNFRI exocytosis (and possibly IL- 6, IL-1RII) thereby prolonging TNF (IL-6, IL-1) signaling and promoting alcohol-induced HCC (AIM2). Our findings will be translated into humans by characterization of IL-17RA-TNFRI-signaling pathways in archived human livers from HCC patients with ALD. We will test if therapeutic blocking of the key IL-17 signaling molecules (IL-17RA, TNFRI, ARTS-1, and DHCR7) specifically in hepatocytes using N-acetylgalactosamine (GalNAc)-conjugated antisense RNA oligonucleotides (ASOs) can effectively suppress steatosis, fibrosis, and HCC in WT mice with NASH and ALD (AIM3). If proven, hepatocyte-specific blocking of IL-17 signaling using GalNAc-ASOs can provide a new strategy for HCC treatment in ALD and NASH patients.

摘要：肝细胞癌是由肝炎病毒、非酒精性脂肪性肝炎、以及酒精性肝病(ALD)，通常从肝纤维化发展到肝硬变和癌症。我们的初步数据显示，脂肪变性肝细胞中IL-17信号的基因缺失显著减轻ALD损伤小鼠肝细胞癌的发展，提示IL-17信号转导是抗肝癌的靶点肝细胞癌治疗。我们的中心假设是IL-17信号调节趋化因子的产生，从头开始脂肪变性肝细胞的脂肪生成和TNFRI的表达/更新。IL-17信号促进ALD-和 NASH通过激活肿瘤坏死因子/TnFRI-SREBP1/2-HcR7-胆固醇的合成和抑制而诱导肝癌 ARTS-1/NUC2依赖的TNFRI胞吐作用。这项研究的目的是通过以下方式来描述这种机制其中IL-17A/IL-17RA信号调节代谢损伤肝细胞的反应，并比较 ALD和NASH模型中IL-17信号转导途径的研究策略：应对IL-17 ALD和NASH损伤的WT和肝细胞特异性IL-17RA的信号将同时进行比较肝细胞癌基因敲除小鼠。我们确定在NASH和ALD损伤中IL-17信号是否被类似地激活肝细胞。我们确定阻断脂肪变性肝细胞中的IL-17信号是否足以抑制肝癌新陈代谢受损的肝脏中。尤其是IL-17在DEN-OR(MUP-uPA)发病机制中的作用。将在WT和肝细胞特异性IL-17RA基因敲除小鼠中研究ALD和NASH损伤诱导的肝癌 (IL-17RAΔ-HEP小鼠)。肝细胞癌、炎症、脂肪变性和肝纤维化的发展将跨越所有人群老鼠。WT和IL-17RA缺陷型AFP+YAP+肝细胞癌的诱变及脂肪变性肝细胞对将对IL-17A进行表征。具体地说，我们确定趋化因子分泌、胆固醇合成是否在代谢受损的IL-17RA缺陷肝细胞(AIM1)中被抑制。我们将通过以下方式测试一个新的假设哪种IL-17信号促进TNF/TNFRI-Caspase2-SP1-SREBP1/2-DHCR7-dependent胆固醇通过阻断ARTS-1-NUCB2调节的TNFRI胞吐(可能还有IL-2)合成脂肪变性肝细胞 6，IL-1RII)，从而延长肿瘤坏死因子(IL-6，IL-1)信号转导通路，促进酒精性肝细胞癌的发生。我们的这些发现将通过对存档的IL-17RA-TNFRI信号通路的表征而被翻译到人类身上肝细胞癌合并酒精性肝病患者的人肝。我们将测试是否对关键的IL-17信号进行治疗阻断利用N-乙酰半乳糖胺在肝细胞中特异性表达的分子(IL-17RA、TNFRI、ARTS-1和DHCR7) (GalNAc)偶联反义RNA寡核苷酸(ASO)可有效抑制脂肪变性、纤维化和 NASH和ALD(AIM3)WT小鼠的肝癌模型。如果证实，肝细胞特异性阻断IL-17信号转导使用 GalNAc-ASOS可为ALD和NASH患者的肝细胞癌治疗提供新的策略。