Apoptosis Effectors Targeted By Hedgehog-Supported MicroRNAs

Hedgehog 支持的 MicroRNA 靶向凋亡效应子

• 批准号: 8309036
• 负责人: Justin L. Mott
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309036
• 关键词: Address; Apoptosis; Apoptotic; BCL2L11 gene; Bile duct carcinoma; Binding; Cell Culture Techniques; Cell Death; Cell Death Signaling Process; Cell Survival; Cells; Cessation of life; Cholangiocarcinoma; Chromosomes, Human, Pair 7; Clinical; Computer Analysis; Cues; Data; Development; Enhancers; Erinaceidae; Figs - dietary; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glioma; Goals; Health; Hepatobiliary; Human; Immune system; Introns; Knowledge; Lead; Ligands; Link; Liver; Maintenance; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Neoplasms; Oncogenic; Pathway interactions; Play; Production; Proteins; Proteome; RNA; Regulation; Research; Resistance; Role; Scientific Advances and Accomplishments; Signal Transduction; Site; Stimulus; TNFRSF10A gene; TNFSF10 gene; Testing; Therapeutic; Transcriptional Activation; base; cancer therapy; cell type; death receptor-4; human TNFRSF10A protein; improved; insight; neoplastic cell; novel; polypeptide; prevent; receptor; research study; smoothened signaling pathway; tool; transcription factor; tumor

DESCRIPTION (provided by applicant): The OVERALL OBJECTIVES of this project are to understand the altered regulation of microRNAs by oncogenic signals in cholangiocarcinoma, and how microRNAs contribute to cell death resistance. Approaches that subvert survival pathways have demonstrated that tumor cells are not endowed with impenetrable armor, but are rather fragile, and dependent on ongoing prosurvival mechanisms. Recently, an RNA-based layer of gene regulation has emerged that promotes tumor cell survival, with a prominent role for microRNAs. MicroRNAs act to fine tune the proteome in a cell-type- and stimulus-specific manner and altered microRNA expression is a feature of human cancers. Sonic Hedgehog, a developmental pathway reactivated in cholangiocarcinoma, may play a role in microRNA alterations. Preliminary studies investigating microRNA targets of Hedgehog signaling have identified three microRNAs, mir-106b, mir-93, and mir-25 that are dependent upon Hedgehog for expression. These microRNAs are clustered on chromosome 7 and collectively referred to as mir-106b~mir-25. Additional preliminary data using computational analysis and cell culture models has confirmed that mir-25 protects cells from TRAIL-induced apoptosis by repressing expression of Death Receptor-4 (one of two pro-apoptotic TRAIL receptors) as well as the pro-apoptotic BH3 protein Bim. Based on these observations, the CENTRAL HYPOTHESIS of this proposal is that Hedgehog signaling protects against TRAIL-induced death via increased expression of mir-106b~mir-25 and reciprocal silencing of key apoptotic signaling polypeptides, DR4 and Bim. The SPECIFIC AIMS are to test the hypotheses that: (1) Hedgehog signaling, by MCM7 host-gene transcription, stimulates mir-106b~mir-25 production; and (2) mir-25, mir-93, and mir-106b protect cells from apoptosis by directly targeting Death Receptor-4 and Bim mRNAs. Advanced molecular and cellular tools to manipulate microRNAs and Hedgehog signaling have been developed to address these questions of biomedical importance in hepatobiliary neoplasia. The current application seeks to advance the scientific knowledge regarding cell death signaling in cholangiocarcinoma. Thus, the results of the proposed experiments are related to improving health by understanding the altered pathways promoting cell death resistance in liver cancer. Successful completion of this proposal will provide needed mechanistic insight to influence clinical approaches to compel cholangiocarcinoma cell death through Hedgehog inhibition.

描述(由申请人提供)：本项目的总体目标是了解胆管癌细胞中致癌信号对microRNAs的调节变化，以及microRNAs如何参与细胞死亡抵抗。颠覆生存途径的方法已经证明，肿瘤细胞并不是被赋予了坚不可摧的盔甲，而是相当脆弱，并依赖于正在进行的生存机制。最近，一种基于RNA的基因调节层已经出现，它可以促进肿瘤细胞的存活，其中microRNAs的作用尤为突出。MicroRNA以细胞类型和刺激特定的方式微调蛋白质组，而microRNA表达的改变是人类癌症的一个特征。Sonic Hedgehog是胆管细胞癌中重新激活的一种发育途径，可能在microRNA的改变中发挥作用。研究Hedgehog信号的microRNA靶标的初步研究已经确定了三个依赖Hedgehog表达的microRNAs，mir-106b、mir-93和mir-25。这些microRNA聚集在7号染色体上，统称为mir-106b~mir-25。使用计算分析和细胞培养模型的其他初步数据证实，mir-25通过抑制死亡受体-4(两种促凋亡的TRAIL受体之一)以及促凋亡的BH3蛋白Bim的表达来保护细胞免受TRAIL诱导的凋亡。基于这些观察，这一建议的中心假设是Hedgehog信号通过增加mir-106b~mir-25的表达和相互沉默关键的凋亡信号多肽DR4和Bim来保护TRAIL诱导的死亡。其具体目的是验证以下假设：(1)Hedgehog信号通过MCM7宿主基因转录，刺激mir-106b~mir-25的产生；(2)mir-25、mir-93和mir-106b通过直接靶向Death Receptor-4和Bim mRNAs来保护细胞免受凋亡。已经开发了先进的分子和细胞工具来操纵microRNAs和Hedgehog信号，以解决这些在肝胆管肿瘤中具有生物医学重要性的问题。目前的应用旨在促进对胆管癌细胞中细胞死亡信号的科学认识。因此，拟议的实验结果与通过了解促进肝癌细胞死亡抵抗的改变的途径来改善健康有关。这项提案的成功完成将提供所需的机械性见解，以影响通过Hedgehog抑制来迫使胆管癌细胞死亡的临床方法。

项目成果

XIAP antagonist embelin inhibited proliferation of cholangiocarcinoma cells.

• DOI: 10.1371/journal.pone.0090238
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wehrkamp CJ;Gutwein AR;Natarajan SK;Phillippi MA;Mott JL
• 通讯作者: Mott JL

Overview of microRNA biology.

• DOI: 10.1055/s-0034-1397344
• 发表时间: 2015-02
• 期刊: Seminars in liver disease
• 影响因子: 4.2
• 作者: Mohr AM;Mott JL
• 通讯作者: Mott JL

Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis.

• DOI: 10.1038/cddis.2012.74
• 发表时间: 2012-06-28
• 期刊: Cell death & disease
• 影响因子: 9