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Investigation of tumor suppressive miR-148a in IDH mutant gliomas

IDH 突变神经胶质瘤中肿瘤抑制 miR-148a 的研究

基本信息

批准号：
8698183
负责人：
Albert Lai
金额：
$ 31.96万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698183
关键词：
Address Adult Affect Biological Markers Cell Proliferation Cell model Cells Clinical Data CpG Island Methylator Phenotype CpG Islands Cytosine DNA DNA Methylation Data Development Diagnosis Diffuse Disease Down-Regulation Epigenetic Process Event Functional RNA Future Gene Expression Gene Targeting Genes Genomics Glioma Gliomagenesis Growth Hypermethylation Investigation Isocitrate Dehydrogenase Laboratories Lead Link Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Methylation Methyltransferase MicroRNAs Mission Modality Molecular Mutation Normal tissue morphology Outcome Pathway interactions Patients Property Public Health Radiation Research Resolution Role Techniques Testing Therapeutic Tissues Translations Tumor Suppression United States National Institutes of Health base demethylation genome-wide improved in vivo innovation insight methylome mutant neoplastic cell novel novel strategies novel therapeutics pre-clinical programs promoter public health relevance restoration therapeutic target tissue resource tumor tumorigenic

项目摘要

Project Summary/Abstract Gliomas presently remain incurable with currently available radiation and chemotherapeutic modalities. Intensive molecular characterization of gliomas have revealed a rich molecular diversity of aberrations that give rise to the hope that we can significantly impact this disease through translation of the most promising targets into personalized therapies. This proposal directly addresses this need by investigating the tumor suppressive mechanism of a novel target, miR-148a, identified using an innovative and powerful DNA methylation profiling strategy established in the PI's laboratory. Although not yet studied in glioma, miRNA-148a is emerging as a tumor suppressive miRNA in other cancers. As small non-coding RNAs that suppress gene expression, miRNAs occupy key roles in cancer mechanisms and provide emerging therapeutic targets as either themselves or genes they regulate. Extensive genomic characterization of cancer tissue has revealed the widespread presence of aberrant DNA CpG island methylation, which can be associated with the epigenetic silencing of some miRNAs. The recently discovered isocitrate dehydrogenase (IDH) mutation is thought not only to provide a biomarker of secondary gliomas but also represent an initiating event in gliomagenesis. Our research in IDHMUT gliomas has contributed to the recognition of an IDHMUT-associated genome-wide hypermethylation profile, glioma-CpG island methylator phenotype (G-CIMP), that is not found in normal tissue or IDH wild-type gliomas. This has led to a widely accepted but as yet unsupported hypothesis that G-CIMP occupies a pivotal role in gliomagenesis through silencing of tumor suppressive genes and/or genes involved in differentiation. Thus, we hypothesized that IDHMUT-associated DNA hypermethylation may silence the expression of important tumor-suppressive miRNAs in glioma. As shown in our preliminary data, we used unbiased methylation profiling to identify hypermethylated miRNA genes in the context of G-CIMP, and among these candidates, miRNA-148a appears not only to have tumor suppressive properties but also to directly regulate DNMT1, a key gene involved in DNA methylation maintenance. In this proposal, we test the central hypotheses that IDHMUT causes epigenetic silencing of the tumor suppressive miR-148a and that re-expression of miR-148a provides a novel strategy for glioma treatment, particularly for the IDHMUT subset. To do so, the aims are: 1) to investigate the molecular basis linking IDH mutation and miR148a downregulation, 2) to establish miR-148a downstream target genes contributing to tumor suppression, and 3) to explore the therapeutic potential of miR-148a in IDHMUT glioma. These aims will be accomplished combining an unbiased high-resolution methylation profiling technique, extensive patient tissue resources, and a variety of cell models including patient-derived glioma neurospheres cells. Accomplishment of the stated aims will have a significant contribution towards the development of novel tailored treatments for gliomas based on restoration of deficient miRNAs.

项目总结/文摘