Liver Cancer Therapy by MiR-22 and Its Inducers

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 (肝癌)是一种致命的疾病，治疗选择有限。使用像索拉非尼这样的药物，肝癌将 永远不要治疗；它只能在几个月内得到控制。这样的结果并不能证明其高昂的价格是合理的， 每位患者每月最高可达5000美元。有效的癌症治疗策略应该通过以下方式来针对这些途径 哪种癌症是首先出现的。重要的是要注意到，肝脏不断地暴露在各种类型的 来自肠道的化学物质，因为超过70%的肝脏血液来自肠道 肠肝循环。新出现的证据还表明，肠道微生物区系不仅与结肠有关 癌症，但也影响肝脏炎症和肝癌的发生。拟议中的项目针对的是一种肿瘤 抑制子，即miR-22，它是由有益的化学物质诱导的，通常存在于肝脏和肠道。 含有HDAC(组蛋白脱乙酰酶)的胆汁酸(BAS)、维甲酸(RA)和短链脂肪酸(SCFA) 抑制器属性。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， 而且还提供预防手段，阻止癌症复发，从而制定有效的治疗策略。至 了解肠道衍生信号如何影响肝癌的发生，我们发现miR-22一直是 在肝细胞癌和结肠癌标本中均降低。此外，我们的新奇数据还显示， BA受体FXR(法尼醇X受体)、SCFA受体Gpr41、43和109A的表达水平， 以及维甲酸产生剂ALDH1A1(乙醛脱氢酶1A1)和维甲酸氧化酶CYP26A1， 在人类肝细胞癌和结肠癌标本中都降低了。此外，FXR基因敲除小鼠，有 MiR-22减少和BA合成失调，自发发展为肝癌。此外，我们令人兴奋的是 初步数据显示，miR-22是一种乙酰化修饰剂，也是细胞周期阻滞剂，因为它能够 减少HDAC1、HDAC4、SIRT1和SRC1以及细胞周期蛋白A2的表达。要有一个全面的 了解miR-22在肝癌中的作用，Aim 1研究miR-22具有 通过研究miR-22的下游效应来研究其抗癌作用。目的2研究miR-22的作用 利用原位肝癌模型治疗肝癌中的模拟药物和抑制剂。目标3分析了 MIR-22诱导剂包括合成的FXR激动剂乙酰胆酸和RA+SCFA的组合。 丙酸在肝癌治疗中的应用。此外，我们将研究miR-22的作用，包括miR-22抑制剂或 在治疗过程中的模仿者。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生成的有前景的数据 细胞系、小鼠和人类样本，我们相信产生的数据将推动肝脏领域的发展 癌症治疗。

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.