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A20 Promotes Glioma Stem Cell Mediated Tumorigenesis

A20 促进神经胶质瘤干细胞介导的肿瘤发生

基本信息

批准号：
8494594
负责人：
Anita Borton Hjelmeland
金额：
$ 22.23万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494594
关键词：
Adjuvant Adult Animal Model Apoptosis Apoptosis Inhibitor Apoptotic BIRC5 gene Binding Biological Brain Neoplasms Cell Cycle Arrest Cell Death Cell Survival Cells DNA Damage DNA damage checkpoint Data Databases Endothelial Cells Excision Gene Cluster Gene Targeting Glioblastoma Glioma Growth Human Hypoxia Link Maintenance Malignant Neoplasms Mediating Messenger RNA Microarray Analysis Modeling Molecular Mus Nature Operative Surgical Procedures Patients Pattern Phenotype Phosphorylation Primary Brain Neoplasms Property Proteins Radiation Radiation Induced DNA Damage Recurrence Reporting Resistance Response Elements Role Signal Pathway Signal Transduction Stem cells TNF gene Therapeutic Therapeutic Studies Transcriptional Activation Tumor Angiogenesis Tumor Necrosis Factor-alpha Vascular Endothelial Growth Factors Xenograft procedure angiogenesis bHLH-PAS factor HLF base cancer stem cell cell growth regulation chemoradiation chemotherapy genetic manipulation inhibitor/antagonist neoplastic cell novel promoter response self-renewal small hairpin RNA stem cell biology temozolomide transcription factor tumor tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY Glioblastomas are the most common and aggressive primary brain tumor in adults, with a median survival of only fourteen months with the best available treatments. Much needed novel therapies may arise from increased appreciation of the biological and molecular properties of subset of tumor cells which can self-renew and recapitulate the parental tumor. These cancer stem cells remain controversial due to the evolving understanding of their nature: however, a number of reports have demonstrated that glioblastomas contain cancer stem cells and that these glioma stem cells contribute to therapeutic resistance and tumor angiogenesis. We now demonstrate that the cell survival regulator A20/Tumor Necrosis Factor a Inducible Protein 3 is a glioma stem cell target which contributes to glioma growth. Although very limited and often contradictory data exists regarding the expression and function of A20 in brain tumors, we find that GSCs consistently express elevated levels of A20 in comparison to non-stem glioma cells. Targeting the expression of A20 in GSCs reduces their growth in association with increased cell cycle arrest, elevated apoptosis, and decreased self-renewal. Targeting A20 in GSCs increased the survival of mice bearing human glioma xenografts, and analysis of a glioma expression database indicates that increased A20 mRNA correlates with poor glioma patient survival. Based on this background, we hypothesize that A20 promotes glioma growth and recurrence due, in part, to maintenance of a cancer stem cell phenotype. We propose to elucidate the molecular and biological role of A20 in glioma stem cell biology in an effort to determine novel targets for glioma patient therapies.

项目总结