Liver Cancer Therapy by MiR-22 and Its Inducers

MiR-22 及其诱导剂治疗肝癌

• 批准号: 10556373
• 负责人: Yu-Jui Yvonne Wan
• 金额: $ 42.53万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556373
• 关键词: Acetylation; Acids; Affect; Agonist; Apoptosis; BAY 54-9085; Bile Acid Biosynthesis Pathway; Bile Acids; Blood; Butyrates; Cancer Etiology; Cell Cycle; Cell Line; Cell Survival; Cells; Chemicals; Chenodeoxycholic Acid; Clinic; Colon; Colon Carcinoma; Data; Deacetylase; Disease; Enterohepatic Circulation; Enzymes; Exposure to; FFAR3 gene; Fatty Acids; Gene Expression; Goals; HCT116 Cells; HDAC1 gene; HDAC4 gene; Hepatic; Hepatocarcinogenesis; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Incidence; Knockout Mice; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metabolic syndrome; Modification; Molecular; Monitor; Mus; Nuclear Receptors; Obesity; Organ; Outcome; Outcome Study; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Prevention; Preventive; Price; Primary carcinoma of the liver cells; Production; Property; Propionates; Proteins; Retinoic Acid Receptor; Role; SIRT1 gene; Signal Transduction; Sleeping Beauty; Specimen; TP53 gene; Time; Transposase; Tretinoin; Tumor Suppressor Proteins; Tumor Weights; Valerates; Volatile Fatty Acids; Xenograft procedure; aldehyde dehydrogenases; anti-cancer; beta catenin; cancer cell; cancer therapy; carcinogenesis; combat; cyclin A2; effective therapy; gut microbiota; inhibitor; liver cancer model; liver inflammation; mouse model; nonalcoholic steatohepatitis; novel; overexpression; oxidation; receptor; retinoic acid 4-hydroxylase; treatment strategy

PROJECT ABSTRACT The incidence of liver cancer is rising because of obesity and metabolic syndrome. Hepatocellular carcinoma (HCC) is a deadly disease with limited treatment options. Using a drug such as sorafenib, liver cancer will never be treated; it can only be controlled by a couple months. Such outcome does not justify its high price, at up to $5,000 per patient per month. An effective cancer treatment strategy should target the pathways by which cancer arises in the first place. It is important to note that the liver is constantly exposed to all types of chemicals generated from the gut because more than 70% of hepatic blood comes from the gut via enterohepatic circulation. Emerging evidence also reveals that gut microbiota are not only implicated in colon cancer, but also affect hepatic inflammation and liver carcinogenesis. The proposed project targets a tumor suppressor i.e. miR-22, which is induced by the beneficial chemicals normally presents in the liver and gut i.e. bile acids (BAs), retinoic acid (RA), and short chain fatty acids (SCFAs) that have HDAC (histone deacetylase) inhibitor property. Thus, using miR-22 and its inducers not only can induce cancer cell apoptosis and arrest, but also provide preventive means to stop cancer reoccurrence leading to an effective treatment strategy. To understand how gut-derived signaling affects liver carcinogenesis, we uncovered that miR-22 is consistently reduced in both HCC and colon cancer specimens. In addition, our novel data also revealed that the expression levels of BA receptor FXR (farnesoid x receptor), SCFA receptors including GPR41, 43, and 109A, as well as ALDH1A1 (aldehyde dehydrogenase 1A1), a RA generator, and CYP26A1, a RA oxidation enzyme, were all reduced in both human HCC and colon cancer specimens. Moreover, FXR knockout mice, which had reduced miR-22 and dysregulated BA synthesis, spontaneously develop liver cancer. Furthermore, our exciting preliminary data revealed that miR-22 is an acetylation modifier as well as cell cycle arrestor due to its ability to reduce HDAC1, HDAC4, SIRT1, and SRC1 as well as CYCLIN A2 proteins. To have a comprehensive understanding of the effect of miR-22 in liver cancer, Aim 1 studies the mechanism by which miR-22 has an anti-cancer property by investigating the downstream effects of miR-22. Aim 2 studies the effect of miR-22 mimics and inhibitors in HCC treatment using an orthotopoic liver cancer model. Aim 3 analyzes the effect of miR-22 inducers including a synthetic FXR agonist obeticholic acid and a combination RA plus a SCFA i.e. propionate in HCC treatment. Additionally, we will study the role of miR-22 by including miR-22 inhibitors or mimics in the treatment. Furthermore, the molecular mechanism by which acetylation mediates the anti-cancer action of miR-22 and it inducers will be analyzed. Based on the promising data generated using liver and colon cell lines, mice, and human specimens, we are confident that the generate data will advance the field of liver cancer treatment.

项目摘要 由于肥胖和代谢综合征，肝癌的发病率正在上升。肝细胞癌 （HCC）是一种致命的疾病，治疗选择有限。使用索拉非尼等药物会导致肝癌 永远不会受到治疗；只能控制几个月。这样的结果并不能证明其高价是合理的 每个患者每月最多 5,000 美元。有效的癌症治疗策略应针对以下途径： 哪种癌症首先出现。值得注意的是，肝脏不断暴露于各种类型的环境中。 肠道产生的化学物质，因为超过 70% 的肝血来自肠道 肠肝循环。新的证据还表明，肠道微生物群不仅与结肠有关 癌，还影响肝脏炎症和肝癌的发生。拟议的项目针对肿瘤 抑制因子，即 miR-22，它是由肝脏和肠道中通常存在的有益化学物质（即 miR-22）诱导的。 胆汁酸 (BA)、视黄酸 (RA) 和具有 HDAC（组蛋白脱乙酰酶）的短链脂肪酸 (SCFA) 抑制剂性质。因此，使用miR-22及其诱导剂不仅可以诱导癌细胞凋亡和停滞， 还提供预防手段来阻止癌症复发，从而形成有效的治疗策略。到 为了了解肠源性信号传导如何影响肝癌发生，我们发现 miR-22 始终如一 HCC 和结肠癌标本中的含量均有所减少。此外，我们的新颖数据还表明 BA 受体 FXR（法尼醇 X 受体）、SCFA 受体（包括 GPR41、43 和 109A）的表达水平， 以及 ALDH1A1（醛脱氢酶 1A1）（一种 RA 发生器）和 CYP26A1（一种 RA 氧化酶）， 在人类肝癌和结肠癌样本中均有所减少。此外，FXR 基因敲除小鼠 miR-22 减少和 BA 合成失调，自发发展为肝癌。此外，我们激动人心的 初步数据显示，miR-22 是一种乙酰化修饰剂以及细胞周期阻滞剂，因为它能够 减少 HDAC1、HDAC4、SIRT1 和 SRC1 以及 CYCLIN A2 蛋白。要有一个全面的 为了了解 miR-22 在肝癌中的作用，目标 1 研究 miR-22 发挥作用的机制 通过研究 miR-22 的下游效应来确定其抗癌特性。目标 2 研究 miR-22 的作用 使用原位肝癌模型治疗 HCC 的模拟物和抑制剂。目标 3 分析效果 miR-22 诱导剂包括合成 FXR 激动剂奥贝胆酸和 RA 加 SCFA 的组合，即 丙酸盐在 HCC 治疗中的应用此外，我们将通过加入 miR-22 抑制剂或 治疗中模仿。此外，乙酰化介导抗癌的分子机制 将分析 miR-22 及其诱导剂的作用。基于使用肝脏和结肠产生的有希望的数据 细胞系、小鼠和人类样本，我们相信生成的数据将推动肝脏领域的发展 癌症治疗。

项目成果

Obesity treatment by epigallocatechin-3-gallate-regulated bile acid signaling and its enriched Akkermansia muciniphila.

表没食子儿茶素-3-没食子酸酯调节胆汁酸信号传导及其富集的阿克曼氏菌（Akkermansia muciniphila）治疗肥胖。

• 发表时间: 2018-06-08
• 作者: Sheng, Lili;Jena, Prasant Kumar;Liu, Hui;Hu, Ying;Nagar, Nidhi;Bronner, Denise N;Settles, Matthew L;Bäumler, Andreas J;Wan, Yu
• 通讯作者: Wan, Yu

Regulation of bile acid receptor activity☆.

胆汁酸受体活性的调节。

• 发表时间: 2018-12
• 作者: Wan, Yu;Sheng, Lili
• 通讯作者: Sheng, Lili

Hepatocellular carcinoma diagnosis and treatment: An overview.

肝细胞癌的诊断和治疗：概述。

• 发表时间: 2020-12
• 作者: Colquhoun, Steven D;Wan, Yu
• 通讯作者: Wan, Yu

Long-term Western diet intake leads to dysregulated bile acid signaling and dermatitis with Th2 and Th17 pathway features in mice.

长期西方饮食摄入会导致小鼠胆汁酸信号失调和具有 Th2 和 Th17 通路特征的皮炎。

• DOI: 10.1016/j.jdermsci.2019.05.007
• 发表时间: 2019-07-01
• 期刊: Journal of dermatological science
• 影响因子: 4.6
• 作者: P. Jena;Lili Sheng;Kyle Mcneil;T. Chau;Sebastian Yu;M. Kiuru;M. Fung;S. Hwang;Y. J. Wan
• 通讯作者: Y. J. Wan

Erratum to The UVA-induced long non-coding RNA GS1-600G8.5 regulates the expression of IL-8, J. Dermatol. Sci. 90 June (3) (2018) 363-366.

UVA 诱导的长非编码 RNA GS1-600G8.5 调节 IL-8 表达的勘误，J. Dermatol。

• 发表时间: 2018-06-06
• 影响因子: 4.6
• 作者: Yo, Kazuyuki;Rünger, Thomas M
• 通讯作者: Rünger, Thomas M