Role of microRNAs in intestinal stem cell regulation and cancer initiation

 描述(申请人提供)：WNT/？-catenin信号对肠道干细胞(ISCs)的维持和激活至关重要。导致未受调控的Wnt/？-catenin的突变与肿瘤的启动和生长有关。最近的证据表明，这一途径也可能是ISCs向肿瘤干细胞(CSCs)转变的关键介质，CSCs具有干细胞样的特征，并有助于转移和耐药。规范的Wnt信号介导肿瘤形成的潜在机制在很大程度上是未知的，但新的证据表明，APC的缺失或ç-catenin的稳定导致了microRNAs(MiRNAs)的异常表达。MiRNAs是一类高度保守的非编码小RNA(约22个核苷酸长)，已被证明在细胞内稳态和发育中发挥关键作用，也可能有助于癌症的发生。MiRNAs是否直接介导了Lgr5+ISCs的转化还没有被探索。为了研究miRNAs在Wnt介导的肿瘤形成中的作用，我们进行了肠隐窝miRNA表达的全球图谱分析，以稳定？-catenin。我们的分析确定了五个差异表达的miRNAs(let-7E、miR-96、miR-223、miR-411和miR-423-5p)，并确定了miRNAs下调的总体趋势，这是在人类癌症中观察到的现象。以下特定目的旨在进一步研究miRNAs在肠道干细胞调控和癌症发生中的作用。目的1.研究全球隐蔽图谱鉴定的特定miRNAs在 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。综上所述，这项建议试图描述miRNAs及其靶点在ISC行为和腺瘤形成中的作用。我们期望这将为基于WNT的新型肠癌生物标记物和治疗药物的开发提供基础。

 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.