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

描述(由申请人提供)：“肿瘤场效应”是指在肿瘤发展之前和易于发生的肿瘤前病变的存在。尽管这些癌前细胞在组织学上可能是正常的，但它们往往含有肿瘤特有的突变或表观遗传学变化。在肿瘤前细胞中识别这种早期致癌事件，将加深我们对肿瘤发生的分子基础的理解。此外，它还可能为肿瘤的治疗和预防提供方法。在髓母细胞瘤小鼠模型中，肿瘤前病变已经被很好地描述：PTC(Patted，Sonic Hedgehog通路的拮抗剂)杂合子小鼠。此前有报道称，肿瘤前期细胞和终末期肿瘤细胞均缺乏PTC的表达。然而，PTC基因沉默的潜在机制仍不清楚。最近的研究发现，microRNAs抑制了PTC杂合子小鼠肿瘤前细胞和肿瘤细胞中PTC的表达。这一建议将确定PTC沉默在肿瘤前细胞发生中的重要作用，并确定负责抑制肿瘤前细胞中PTC表达的microRNAs。本研究将为髓母细胞瘤的发生发展提供新的认识，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，microoRNA失调代表了肿瘤前细胞的一个重要属性，这对肿瘤的启动是必不可少的。

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.