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：
10463697
负责人：
Tatiana Kisseleva
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/10463697
关键词：
AFP gene Ablation Acetylgalactosamine Address Alcoholic Liver Diseases Alcohols Antisense RNA Archives Attenuated Body mass index CCL2 gene 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 virus Hepatitis Viruses Hepatocyte Human IL17 Signaling Pathway In Vitro Incidence Inflammation Injury Interleukin-1 Interleukin-17 Interleukin-6 Interleukins Knock-out Knockout Mice Liver Liver Fibrosis Malignant Neoplasms Mediating Mediator of activation protein 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 TNF gene Testing Therapeutic Translating Up-Regulation Virus Diseases base chemokine exosome gain of function genetic approach hepatocyte injury in vivo inhibitor injured insight lipid biosynthesis liver injury loss of function macrophage 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.

抽象的：肝细胞癌 (HCC) 是由肝炎病毒 HBV/HCV、非酒精性脂肪性肝炎 (NASH)、酒精性肝病（ALD），通常从肝纤维化进展为肝硬化和癌症。初步数据表明，脂肪变性肝细胞中 IL-17 信号传导的基因缺失显着减轻 ALD 损伤小鼠 HCC 的发展，表明 IL-17 信号传导是抗 ALD 损伤的靶标 HCC 治疗。我们的中心假设是 IL-17 信号从头调节趋化因子的产生。脂肪生成和脂肪肝细胞中的 TNFRI 表达/周转可促进 ALD 和 ALD。 NASH 通过激活 TNFα/TNFRI-SREBP1/2-DHCR7-胆固醇合成和抑制诱导 HCC ARTS-1/NUC2 依赖性 TNFRI 胞吐作用的研究目的是通过以下方式表征其机制。 IL-17A/IL-17RA 信号传导调节代谢损伤肝细胞的反应，并比较 ALD 和 NASH 实验模型中 IL-17 信号通路的策略：对 IL-17 的反应。将在 ALD 和 NASH 损伤的 WT 以及肝细胞特异性 IL-17RA 中并排比较信号传导我们确定患有 HCC 的基因敲除小鼠中 IL-17 信号传导在 NASH 和 ALD 损伤中是否同样被激活。我们确定阻断脂肪肝细胞中的 IL-17 信号传导是否足以抑制 HCC 具体而言，IL-17 在 DEN- 或 (Mup-uPA)- 发病机制中的作用。将在 WT 和肝细胞特异性 IL-17RA 敲除小鼠中研究 ALD 和 NASH 损伤中诱导的 HCC （IL-17RAΔHep 小鼠）所有组都会出现 HCC、炎症、脂肪变性和肝纤维化。 WT 和 IL-17RA 缺陷型 AFP+YAP+ HCC 的诱变以及脂肪肝细胞对 AFP+YAP+ HCC 的反应。具体而言，我们将确定趋化因子分泌、胆固醇合成是否存在特征。在代谢损伤的 IL-17RA 缺陷肝细胞 (AIM1) 中受到抑制，我们将通过以下方式检验一个新假设。 IL-17 信号传导促进 TNFα/TNFRI-Caspase2-SP1-SREBP1/2-DHCR7 依赖性胆固醇通过阻断 ARTS-1-NUCB2 调节的 TNFRI 胞吐作用（以及可能的 IL- 6、IL-1RII) 从而延长 TNF (IL-6、IL-1) 信号传导并促进酒精诱发的 HCC (AIM2)。研究结果将通过存档的 IL-17RA-TNFRI 信号通路的表征转化为人类我们将测试是否可以通过治疗阻断关键的 IL-17 信号传导。使用 N-乙酰半乳糖胺特异性地在肝细胞中识别分子（IL-17RA、TNFRI、ARTS-1 和 DHCR7） (GalNAc) 缀合的反义 RNA 寡核苷酸 (ASO) 可以有效抑制脂肪变性、纤维化和患有 NASH 和 ALD 的 WT 小鼠中的 HCC（AIM3）如果得到证实，可使用 IL-17 信号传导进行肝细胞特异性阻断。 GalNAc-ASOs 可以为 ALD 和 NASH 患者的 HCC 治疗提供新策略。