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

• 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
• 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

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。

项目成果

PNPLA3 downregulation exacerbates the fibrotic response in human hepatic stellate cells.

PNPLA3 下调会加剧人肝星状细胞的纤维化反应。

• 发表时间: 2021
• 影响因子: 3.7
• 作者: Rady, Brian;Nishio, Takahiro;Dhar, Debanjan;Liu, Xiao;Erion, Mark;Kisseleva, Tatiana;Brenner, David A;Pocai, Alessandro
• 通讯作者: Pocai, Alessandro