High fat diet induced hepatocyte exosomes-promoted hepatic inflammation and tumorigenesis

高脂饮食诱导肝细胞外泌体促进肝脏炎症和肿瘤发生

• 批准号: 9293342
• 负责人: Zhong-Bin Deng
• 金额: $ 18.92万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9293342
• 关键词: Acceleration; Address; Anti-Inflammatory Agents; Binding Sites; C57BL/6 Mouse; COPS5 gene; Cells; Centers of Research Excellence; Chemoprevention; Chronic; Clinical Treatment; Curcumin; Data; Development; Diet; Diethylnitrosamine; Disease; Elements; Enzymes; Equilibrium; Fatty acid glycerol esters; Fruit; Goals; Growth; Hepatic; Hepatocyte; High Fat Diet; Human; ITGAM gene; Immunosuppression; Immunosuppressive Agents; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Lead; Link; Liver; Liver Extract; Liver neoplasms; MAPK3 gene; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Membrane; Modeling; Molecular Target; Mus; Mutation; Myelogenous; Myeloid Cells; Natural Killer Cells; Obese Mice; Obesity; Pathogenicity; Pathway interactions; Phosphorylation Site; Phosphotransferases; Play; Prevention; Process; Production; Property; Role; Safety; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; T-Lymphocyte; Technology; Testing; Toxicology; Tumor Promotion; Vesicle; base; cancer therapy; cell growth; chemotherapy; cytokine; exosome; in vitro testing; in vivo; knock-down; liver development; macrophage; mouse model; nanoparticle; neoplastic cell; novel; peripheral blood; prevent; response; targeted delivery; tumor; tumor growth; tumor progression; tumorigenesis

ABSTRACT The overall goal of this proposal is to study the role of hepatocyte exosomes in high fat diet mediated promotion of liver cancer development. Further, we will determine whether using novel edible fruit exosomes as a delivery vehicle for targetable delivery of an anti-inflammatory agent to tumor cells for treatment of liver cancer. Our preliminary data has indicated that hepatocyte exosomes are present in the peripheral blood of obese mice and obese individuals and the hepatocyte exosomes from mice fed a high-fat diet (HFD- exosomes) promote inflammatory responses and the growth of liver cancer in mouse model. These data implicate the production of hepatocyte exosomes in the inflammatory responses associated with liver cancer. Our preliminary data indicate that the HFD-exosomes carry high levels of sumoylated CSN5 (sumo-CSN5) and that the delivery of the sumo-CSN5 to immature myeloid promotes the degradation of Jak3, a process that is essential for differentiation of the myeloid cells. This pinpointed the production of the sumo-CSN5 as a critical pathogenic step in exosomes mediated Induction of inflammation cytokines. In hepatocyte cells, ErK1/2 kinase is activated by a soluble factor(s) from the supernatant of liver extracts of high fat-fed mice and causes the disassociation of Senp1 which acts as a suppressor of sumoylation of CSN5, thereby promoting the production of sumo-CSN5. This process is inhibited by curcumin, which is known to inhibit ErK1/2 activation. Therefore, we hypothesize that a high-fat diet promotes the production of exosomes with high levels of sumo-CSN5 by hepatocyte cells; that these exosomes are taken up by immature myeloid cells, resulting in sumo-CSN5- mediated immunosuppression by enhancing degradation of Jak3, and thus the promotion of tumor growth. We further hypothesize that curcumin treatment leads to the inhibition of processing of sumoylation of CSN5 in the hepatocyte cells from mice fed a high-fat diet by inhibition of ErK1/2. These hypotheses will be tested in vitro and in vivo to determine whether: (1) Sumoylated CSN5 in high-fat hepatocyte exosomes is essential for accumulation of activated iMCs and promotion of liver tumor progression; (2) The ErK1/2 signaling pathway determines the balance of desumoylation vs. sumoylation of CSN5 in hepatocyte cells and is promoted by a high-fat diet; and (3) the high-fat diet-induced hepatocyte exosome-mediated promotion of liver tumor growth is reversible by using novel edible fruit exosomes as a delivery vehicle for targetable delivery of an anti- inflammatory agent to inflammatory cells for treatment of cancer. Clinical Relevance. The data generated should identify a novel mechanism that links a high-fat diet to inflammatory and immunosuppressive responses associated with tumor development and thereby identify molecular targets for chemotherapy or chemoprevention. Demonstration of the safety of fruit exosomes-based delivery of curcumin and its targeting to inflammatory cells would be a significant step forward in the treatment of this debilitating disease.

抽象的 该提案的总体目标是研究肝细胞外泌体在高脂饮食中介导的作用 促进肝癌发展。此外，我们将确定是否使用新型食用果实外泌体 作为将抗炎剂靶向输送到肿瘤细胞治疗肝脏的递送工具 癌症。我们的初步数据表明，肝细胞外泌体存在于 肥胖的小鼠和肥胖个体以及喂养高脂饮食的小鼠的肝细胞外泌体（HFD- 外泌体）在小鼠模型中促进炎症反应和肝癌的生长。这些数据 暗示与肝癌相关的炎症反应中肝细胞外泌体的产生。 我们的初步数据表明，HFD诊断携带高水平的Sumoypated CSN5（SUMO-CSN5）和 将SUMO-CSN5传递到未成熟的髓样的髓样会促进JAK3的降解，这是一个过程 髓样细胞的分化至关重要。这将Sumo-CSN5的产生视为关键 外泌体介导的炎症细胞因子诱导的致病步骤。在肝细胞中，ERK1/2激酶 由高脂肪喂养小鼠的肝脏提取物的可溶性因子激活，并导致 SENP1的分离，它充当CSN5的Sumoylation抑制器，从而促进生产 Sumo-CSN5。姜黄素抑制了此过程，姜黄素已知会抑制ERK1/2激活。所以， 我们假设高脂饮食促进了由高脂饮食的产生 肝细胞细胞；这些外泌体被未成熟的髓样细胞吸收，从而导致SUMO-CSN5- 通过增强JAK3的降解，从而促进肿瘤生长来介导的免疫抑制。我们 进一步假设姜黄素治疗会导致抑制CSN5的加工 来自小鼠的肝细胞通过抑制ERK1/2喂养高脂饮食。这些假设将在体外检验 并在体内确定：（1）高脂肝细胞外泌体中的sumoypated csn5对于 激活的IMC的积累和促进肝肿瘤进展； （2）ERK1/2信号通路 确定hepatocyte细胞中desumoylation与CSN5的sumoylation的平衡，并通过A促进 高脂饮食； （3）高脂饮食诱导的肝细胞外泌体介导的肝肿瘤生长的促进 通过使用新型食用果实外泌体作为递送工具可逆的可逆 炎性细胞的炎性剂治疗癌症。临床相关性。生成的数据 应确定一种新型机制，将高脂饮食与炎症和免疫抑制反应联系起来 与肿瘤发育相关，从而确定化学疗法或 化学预防。证明姜黄素基于水果外泌体的安全性及其靶向 炎症细胞将是治疗这种使人衰弱疾病的重要一步。