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

项目成果

Targeting stroma and tumor, silencing galectin 1 treats orthotopic mouse hepatocellular carcinoma.

• DOI: 10.1016/j.apsb.2023.10.010
• 发表时间: 2024-01
• 期刊: Acta pharmaceutica Sinica. B

Hepatocellular carcinoma diagnosis and treatment: An overview.

• DOI: 10.1016/j.livres.2020.11.006
• 发表时间: 2020-12
• 期刊: Liver research
• 作者: Colquhoun SD;Wan YY
• 通讯作者: Wan YY

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。

• DOI: 10.1016/j.jdermsci.2018.05.010
• 发表时间: 2018
• 期刊: Journal of dermatological science
• 影响因子: 4.6
• 作者: Yo,Kazuyuki;Rünger,ThomasM
• 通讯作者: Rünger,ThomasM

Synbiotics Bifidobacterium infantis and milk oligosaccharides are effective in reversing cancer-prone nonalcoholic steatohepatitis using western diet-fed FXR knockout mouse models.

合成生生物杆菌和牛奶的寡糖可有效使用西部饮食喂养的FXR敲除小鼠模型逆转易癌症的非酒精性脂肪性肝炎。

• DOI: 10.1016/j.jnutbio.2018.04.007
• 发表时间: 2018-07
• 期刊: The Journal of nutritional biochemistry
• 作者: Jena PK;Sheng L;Nagar N;Wu C;Barile D;Mills DA;Wan YY
• 通讯作者: Wan YY

Hepatocellular carcinoma immunotherapy: The impact of epigenetic drugs and the gut microbiome.

肝细胞癌免疫疗法：表观遗传药物和肠道微生物组的影响。

• DOI: 10.1016/j.livres.2020.10.001
• 发表时间: 2020-12
• 期刊: Liver research
• 作者: Vaziri F;Colquhoun S;Wan YY
• 通讯作者: Wan YY