Role of microRNAs in intestinal stem cell regulation and cancer initiation

microRNA在肠道干细胞调节和癌症发生中的作用

• 批准号: 9110015
• 负责人: Manasvi S. Shah
• 金额: $ 6.07万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110015
• 关键词: APC2 gene; Address; Biological Models; Cells; Cessation of life; Colorectal; Colorectal Cancer; Development; Down-Regulation; Enzymes; Exhibits; Gene Expression Profiling; Gene Targeting; Goals; Homeostasis; Human; In Vitro; Intestinal Cancer; Intestinal Diseases; Intestinal Neoplasms; Intestines; Investigation; Link; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Molecular; Mus; Mutation; Neoplasm Metastasis; Nucleotides; Organoids; Pathogenesis; Pathway interactions; Play; Prevention; Process; RNA; Regulation; Reporting; Research Proposals; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; Tamoxifen; Testing; Untranslated RNA; adenoma; base; beta catenin; cancer initiation; cancer stem cell; carcinogenesis; cell behavior; design; differential expression; intestinal crypt; loss of function; miRNA expression profiling; mouse model; neoplastic; novel; novel marker; novel therapeutics; prediction algorithm; public health relevance; research study; stem; therapeutic biomarker; transcriptome sequencing; trend; tumor; tumor growth; tumor initiation; tumorigenesis

 DESCRIPTION (provided by applicant): Wnt/ß-catenin signaling is crucial for maintenance and activation of intestinal stem cells (ISCs). Mutations resulting in unregulated Wnt/ß-catenin have been linked to tumor initiation and growth. Recent evidence suggests that this pathway may also be a key mediator of the transition of ISCs to cancer stem cells (CSCs), which exhibit stem like features and contribute to metastasis and resistance to treatment. The underlying mechanisms by which canonical Wnt signaling mediates tumor formation are largely unknown, but emerging evidence suggests that deletion of APC or stabilization of ß-catenin results in aberrant expression of microRNAs (miRNAs). MiRNAs, a diverse class of highly conserved small non-coding RNAs (~22 nucleotides long), have been shown to play a critical role in cellular homeostasis and development and may also contribute to carcinogenesis. Whether miRNAs directly mediate the transformation of Lgr5+ ISCs has not been explored. To investigate the role of miRNAs in Wnt-mediated tumor formation, we performed global profiling of miRNA expression from intestinal crypts following stabilization of ß-catenin. Our analysis identified five miRNAs (let- 7e, miR-96, miR-223, miR-411 and miR-423-5p) that were differentially expressed and identified a general trend towards down-regulation of miRNAs, a phenomenon observed in human cancers. The following specific aims are designed to further investigate the role of miRNAs in the regulation of intestinal stem cells and the initiation of cancer. Aim 1. To investigate the role of specific miRNAs, identified by global crypt profiling, on ISC behavior. Aim 2. To determine the impact of global miRNA down-regulation on ISC behavior and adenoma formation. In summary, this proposal seeks to delineate the role of miRNAs and their targets on ISC behavior and adenoma formation. We anticipate that this could provide the basis for the development of novel Wnt-based biomarkers and therapeutics for intestinal cancer.

 描述（由申请人提供）：Wnt/ß-连环蛋白信号传导对于肠干细胞（ISC）的维持和激活至关重要。导致 Wnt/β-连环蛋白不受调节的突变与肿瘤的发生和生长有关。最近的证据表明，该途径也可能是 ISC 向癌症干细胞 (CSC) 转变的关键介质，癌症干细胞表现出干细胞样特征，并有助于转移和治疗耐药。经典 Wnt 信号传导介导肿瘤形成的潜在机制在很大程度上尚不清楚，但新出现的证据表明，APC 的缺失或 ß-catenin 的稳定会导致 microRNA (miRNA) 的异常表达。 miRNA 是一类高度保守的小非编码 RNA（长约 22 个核苷酸），已被证明在细胞稳态和发育中发挥着关键作用，也可能导致癌症发生。 miRNA 是否直接介导 Lgr5+ ISC 的转化尚未被探索。为了研究 miRNA 在 Wnt 介导的肿瘤形成中的作用，我们对 β-连环蛋白稳定后肠隐窝的 miRNA 表达进行了全局分析。我们的分析确定了 5 种差异表达的 miRNA（let-7e、miR-96、miR-223、miR-411 和 miR-423-5p），并确定了 miRNA 下调的总体趋势，这是在人类癌症中观察到的现象。以下具体目标旨在进一步研究 miRNA 在调节肠道干细胞和癌症发生中的作用。目标 1. 研究通过全局隐窝分析鉴定的特定 miRNA 对 ISC 行为。目标 2. 确定整体 miRNA 下调对 ISC 行为和腺瘤形成的影响。总之，该提案旨在描述 miRNA 及其靶标对 ISC 行为和腺瘤形成的作用。我们预计这可以为开发基于 Wnt 的新型肠癌生物标志物和治疗方法奠定基础。