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(PQD4) MicroRNA Dysregulation in Field Effect is a Prerequisite for Tumorigenesis

(PQD4) 场效应中的 MicroRNA 失调是肿瘤发生的先决条件

基本信息

批准号：
8843399
负责人：
Zeng-Jie Yang
金额：
$ 23.29万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2017-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The "tumor field effect" denotes the presence of pre-neoplastic lesions that precede and predispose to tumor development. Although such pre-neoplastic cells may be histologically normal, they often harbor mutations or epigenetic changes characteristic of the tumor. Identification of such early tumorigenic events in pre-neoplastic cell, will deepen our understanding the molecular basis for tumorigenesis. Moreover, it may provide approaches for tumor treatment and prevention. Pre-neoplastic lesions have been well characterized in medulloblastoma mouse model: Ptc (Patched, the antagonist of sonic hedgehog pathway) heterozygous mice. It has previously reported that both pre-neoplastic cells and end-stage tumor cells lack Ptc expression. However, the underlying mechanisms for the silencing of Ptc gene are still not known. Recent studies have found that microRNAs repress Ptc expression in pre- neoplastic cells and tumor cells in Ptc heterozygous mice. This proposal will determine the important role of Ptc silencing in the tumorigenesis of pre-neoplastic cells, and identify microRNAs that are responsible for repressing Ptc expression in pre-neoplastic cells. This study will provide insights into the medulloblastoma tumorigenesis, and have important implications in medulloblastoma prevention and treatment. More importantly, the studies will demonstrate for the first time that micoRNA dysregulation represents an important property of pre-neoplastic cells that is essential for tumor initiation.

描述（由申请人提供）：“肿瘤场效应”表示存在肿瘤前病变，该病变先于肿瘤发展并易于肿瘤发展。尽管这种肿瘤前细胞在组织学上可能是正常的，但它们常常带有肿瘤特征的突变或表观遗传变化。鉴定肿瘤发生前细胞中的此类早期致瘤事件将加深我们对肿瘤发生的分子基础的理解。此外，它还可以为肿瘤的治疗和预防提供方法。肿瘤前病变已在髓母细胞瘤小鼠模型：Ptc（Patched，音刺猬通路拮抗剂）杂合子小鼠中得到很好的表征。此前已有报道肿瘤前期细胞和终末期肿瘤细胞均缺乏Ptc表达。然而，Ptc基因沉默的潜在机制仍不清楚。最近的研究发现，microRNA 抑制 Ptc 杂合小鼠肿瘤前细胞和肿瘤细胞中的 Ptc 表达。该提案将确定 Ptc 沉默在肿瘤前细胞肿瘤发生中的重要作用，并鉴定负责抑制肿瘤前细胞中 Ptc 表达的 microRNA。这项研究将为髓母细胞瘤的肿瘤发生提供深入的见解，并对髓母细胞瘤的预防和治疗具有重要意义。更重要的是，这些研究将首次证明，micoRNA 失调是肿瘤前期细胞的一个重要特性，对于肿瘤的发生至关重要。