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

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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.