Liver Cancer Therapy by MiR-22 and Its Inducers

MiR-22 及其诱导剂治疗肝癌

• 批准号: 10094055
• 负责人: Yu-Jui Yvonne Wan
• 金额: $ 43.65万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094055
• 关键词: Acetylation; Acids; Affect; Agonist; Apoptosis; BAY 54-9085; Bile Acid Biosynthesis Pathway; Bile Acids; Blood; Butyrates; Cancer Etiology; Cancer Model; Cell Cycle; Cell Line; Cell Survival; Cells; Chemicals; Chenodeoxycholic Acid; Clinic; Colon; Colon Carcinoma; Data; Deacetylase; Disease; Enterohepatic Circulation; Enzymes; Exposure to; FFAR3 gene; Gene Expression; Goals; HCT116 Cells; HDAC1 gene; HDAC4 gene; Hepatic; Hepatocarcinogenesis; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Incidence; Inflammation; 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; base; beta catenin; cancer cell; cancer therapy; carcinogenesis; combat; cyclin A2; effective therapy; gut microbiota; inhibitor/antagonist; mouse model; nonalcoholic steatohepatitis; novel; overexpression; oxidation; receptor; retinoic acid 4-hydroxylase; therapeutic miRNA; 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)是一种治疗方法有限的致命疾病。使用索拉非尼等药物，肝癌将 无法治疗，只能控制几个月。这样的结果并不能证明其高昂的价格， 每名病人每月最高可达5,000元。有效的癌症治疗策略应该通过以下方式靶向这些途径： 哪一种癌症首先出现。重要的是要注意，肝脏不断暴露于各种类型的 化学物质从肠道产生，因为超过70%的肝血来自肠道， 肝肠循环新出现的证据还表明，肠道微生物群不仅与结肠有关， 癌症，而且还影响肝脏炎症和肝癌的发生。该项目的目标是肿瘤 抑制剂即miR-22，其由通常存在于肝脏和肠道中的有益化学物质诱导，即 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） 抑制剂性能。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， 而且还提供阻止癌症复发的预防手段，从而导致有效的治疗策略。到 了解肠道来源的信号如何影响肝癌发生，我们发现miR-22始终是 在HCC和结肠癌标本中均降低。此外，我们的新数据还显示， BA受体FXR（法尼醇x受体）、SCFA受体（包括GPR 41、43和109 A）的表达水平， 以及ALDH 1A 1（醛脱氢酶1A 1），一种RA发生剂，和CYP 26 A1，一种RA氧化酶， 在人HCC和结肠癌标本中均降低。此外，FXR基因敲除小鼠， 减少的miR-22和失调的BA合成，自发地发展肝癌。此外，我们令人兴奋的 初步数据显示，miR-22是一种乙酰化修饰剂，也是一种细胞周期调节剂， 减少HDAC 1、HDAC 4、SIRT 1和SRC 1以及细胞周期蛋白A2蛋白。有一个全面 为了进一步了解miR-22在肝癌中的作用，目的1研究miR-22在肝癌中的作用机制。 通过研究miR-22的下游作用来研究其抗癌特性。目的2研究miR-22在肿瘤细胞中的作用 使用原位肝癌模型治疗肝癌的模拟物和抑制剂。目标3分析了 miR-22诱导剂，包括合成的FXR激动剂奥贝胆酸和RA加SCFA的组合，即 丙酸在肝癌治疗中的应用此外，我们将通过包括miR-22抑制剂或 在治疗中模仿。此外，乙酰化介导抗癌作用的分子机制 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，小鼠和人类标本，我们相信，产生的数据将推动肝脏领域的发展。 癌症治疗