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

描述（由申请人提供）：“肿瘤场效应”是指在肿瘤发生之前和易发生肿瘤的肿瘤前病变的存在。虽然这些肿瘤前细胞在组织学上可能是正常的，但它们通常含有肿瘤特征的突变或表观遗传变化。在肿瘤前细胞中识别这些早期致瘤事件，将加深我们对肿瘤发生的分子基础的理解。此外，它可能为肿瘤的治疗和预防提供途径。瘤前病变在成神经管细胞瘤小鼠模型Ptc （Patched， sonic hedgehog通路拮抗剂）杂合小鼠中得到了很好的表征。以前有报道称，肿瘤前细胞和终末期肿瘤细胞都缺乏Ptc的表达。然而，Ptc基因沉默的潜在机制尚不清楚。最近的研究发现，在Ptc杂合小鼠的肿瘤前细胞和肿瘤细胞中，microrna抑制Ptc的表达。本课题将确定Ptc沉默在癌前细胞肿瘤发生中的重要作用，并鉴定在癌前细胞中抑制Ptc表达的microrna。本研究将为髓母细胞瘤的发生机制提供新的认识，对髓母细胞瘤的防治具有重要意义。更重要的是，这些研究将首次证明micoRNA失调代表了肿瘤前细胞的一个重要特性，对肿瘤的发生至关重要。

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.