Regulation of microRNA silencing by tumor suppressor PTEN in stem cells

描述(申请人提供)：越来越多的证据表明，各种人类癌症起源于癌症干细胞(CSC)，原因是它们有能力劫持正常胚胎或成人干细胞所使用的自我更新途径。在人类癌症中，WNT、BMI1、Notch、Hedgehog和PTEN通路经常被解除调控，这些通路对干细胞的自我更新至关重要。最近，microRNAs还被证明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CSCs中某一特定途径的解除调控如何在肿瘤发生过程中影响其他途径，目前仍然知之甚少。利用遗传筛选，我们确定了肿瘤抑制基因PTEN的一个新功能，它是胚胎干细胞中microRNA沉默途径的修饰物。PTEN缺失突变与多种人类癌症有关。因此，本项目的目标是阐明PTEN调节干细胞中microRNA沉默机制的有效性的分子机制，并确定microRNAs在PTEN缺失癌细胞恶性转化中的作用。通过研究正常干细胞和PTEN阴性干细胞的microRNA沉默机制的差异，我们希望开发针对PTEN缺失的肿瘤干细胞的新的治疗策略。

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.