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（由应用提供）：Wnt/ß-catenin信号传导对于维持和激活肠道干细胞（ISC）至关重要。导致不受管制的Wnt/ß-catenin的突变与肿瘤的启动和生长有关。最近的证据表明，该途径也可能是ISC向癌症干细胞（CSC）过渡（CSC）的关键介体，该途径表现出类似于特征的茎，并有助于转移和对治疗的耐药性。规范Wnt信号传导介导肿瘤形成的基本机制在很大程度上是未知的，但是新出现的证据表明，APC的缺失或β-catenin的稳定导致microRNAS（miRNA）的异常表达。 miRNA是一种高度保守的小型非编码RNA（〜22个核苷酸）的潜水类别，已被证明在细胞稳态和发育中起着至关重要的作用，也可能有助于致癌。 miRNA是否直接介导了LGR5+ ISC的转化。为了研究miRNA在Wnt介导的肿瘤形成中的作用，我们在β-catenin稳定后从肠道隐窝中对miRNA表达进行了全球分析。我们的分析确定了五个miRNA（let-7e，miR-96，miR-223，miR-411和miR-423-5p），它们的表达方式有所不同，并确定了在人类癌症中观察到的miRNAS下调的一般趋势。以下特定目的旨在进一步研究miRNA在肠道干细胞调节和癌症的主动性中的作用。目的1。研究特定miRNA的作用，通过全球加密分析确定 ISC行为。目的2。确定全球miRNA下调对ISC行为和腺瘤形成的影响。总而言之，该提案旨在描述miRNA及其目标对ISC行为和腺瘤形成的作用。我们预计这可以为开发新型WNT的生物标志物和肠癌治疗的基础提供基础。