Regulation of microRNA silencing by tumor suppressor PTEN in stem cells

干细胞中抑癌基因 PTEN 对 microRNA 沉默的调节

• 批准号: 8301405
• 负责人: XIAOZHONG ALEC WANG
• 金额: $ 20.16万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301405
• 关键词: Affect; Apoptosis; Attenuated; BMI1 gene; Biological Assay; Cell Maintenance; Cell Proliferation; Cell Survival; Cells; Complex; Critical Pathways; Data; Defect; Embryo; Erinaceidae; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Screening; Growth; Homologous Gene; Human; Immunoprecipitation; Individual; Investigation; Knock-out; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Monitor; Mus; Mutation; Neoplasm Metastasis; Normal Cell; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Polyribosomes; Population; Proteins; RNA Interference; Recruitment Activity; Regulation; Reporter; Reporter Genes; Repression; Role; Signal Pathway; Stem cells; Testing; Translations; Tumor Suppressor Genes; Tumor Suppressor Proteins; Up-Regulation; adult stem cell; cancer cell; cancer stem cell; cancer therapy; combinatorial; crosslink; design; embryonic stem cell; genome-wide; human FRAP1 protein; notch protein; novel; novel therapeutics; research study; self-renewal; small hairpin RNA; stem cell biology; therapeutic development; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Accumulating evidence suggests that a variety of human cancers originate from the cancer stem cells (CSC) as a result of their ability to hijack self-renewal pathways that are employed by normal embryonic or adult stem cells. WNT, BMI1, Notch, Hedgehog and PTEN pathways are often deregulated in human cancer and these pathways are critical for the self-renewal of stem cells. More recently, microRNAs have also been shown to regulate many important aspects of stem cell biology and tumorigenesis including proliferation, differentiation, apoptosis, invasion and metastasis. However, it still remains poorly understood how these different self-renewal pathways interact with each other to coordinate self-renewal in normal stem cells and how the deregulation of one particular pathway in CSCs affects other pathways during tumorigenesis. Using a genetic screen, we identified a novel function for the tumor suppressor PTEN as a modifier of the microRNA silencing pathway in embryonic stem cells. Loss-of-PTEN mutations have been associated with a wide range of human cancers. Thus, the objectives of this project are to elucidate the molecular mechanisms by which PTEN modulates the efficacy of microRNA silencing machinery in stem cells and to determine the contribution of microRNAs to drive malignant transformation in loss-of-PTEN cancer cells. By characterizing the difference of microRNA silencing mechanisms between normal and PTEN negative stem cells, we hope to develop new therapeutic strategies that specifically target loss-of- PTEN cancer stem cells. PUBLIC HEALTH RELEVANCE: Understanding the similarities and differences between self-renewal mechanisms in normal stem cells and cancer stem cells offers great promises for better treatment of cancer. The tumor suppressor PTEN (phosphatase and tension homolog) pathway has been shown to control normal stem cell maintenance and self-renewal, whereas the loss of PTEN, frequently found in human cancers, promotes the propagation of cancer stem cells and tumor formation. In this study, we will define a novel modifier function of PTEN in the microRNA silencing pathway, and provide a new avenue to distinguish PTEN- negative cancer stem cells versus normal stem cells.

描述（由申请人提供）：越来越多的证据表明，多种人类癌症起源于癌症干细胞（CSC），因为它们能够劫持正常胚胎或成体干细胞所采用的自我更新途径。WNT、BMI1、Notch、Hedgehog和PTEN通路在人类癌症中通常是失调的，这些通路对于干细胞的自我更新至关重要。最近，microRNA也被证明可以调节干细胞生物学和肿瘤发生的许多重要方面，包括增殖、分化、凋亡、侵袭和转移。然而，这些不同的自我更新途径如何相互作用以协调正常干细胞中的自我更新以及肿瘤发生期间CSC中一种特定途径的失调如何影响其他途径仍然知之甚少。使用遗传筛选，我们确定了肿瘤抑制因子PTEN作为胚胎干细胞中microRNA沉默途径的修饰剂的新功能。失PTEN突变与多种人类癌症相关。因此，该项目的目标是阐明PTEN调节干细胞中microRNA沉默机制的分子机制，并确定microRNA对驱动PTEN缺失癌细胞恶性转化的贡献。通过表征正常和PTEN阴性干细胞之间microRNA沉默机制的差异，我们希望开发新的治疗策略，专门针对PTEN缺失的癌症干细胞。 公共卫生相关性：了解正常干细胞和癌症干细胞自我更新机制之间的相似性和差异，为更好地治疗癌症提供了巨大的希望。肿瘤抑制因子PTEN（磷酸酶和张力同源物）途径已被证明控制正常干细胞的维持和自我更新，而在人类癌症中经常发现的PTEN的缺失促进癌症干细胞的增殖和肿瘤形成。在这项研究中，我们将确定一个新的修饰功能的PTEN的microRNA沉默途径，并提供一个新的途径来区分PTEN阴性的癌症干细胞与正常干细胞。