Mechanism for miR-21-modulated radioresistance

miR-21 调节的放射抗性机制

基本信息

批准号：
8976599
负责人：
YA WANG
金额：
$ 20.36万
依托单位：
EMORY UNIVERSITY
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：
2014-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8976599
关键词：
Affect Aftercare Antisense RNA Apoptosis Biological Assay Cancer Control Cells Cyclin D1 DNA Double Strand Break DNA Repair Pathway DNA damage checkpoint Data Development Double Strand Break Repair DsRed Embryo Fibroblasts Genes Health Human Ionizing radiation Knock-in Knockout Mice Knowledge Luciferases Malignant Neoplasms Mammalian Cell Mediating MicroRNAs Modeling Mouse Strains Mus Nonhomologous DNA End Joining Pathway interactions Phosphorylation Site Play Proteins Publications Radiation Tolerance Radiation therapy Radioresistance Reagent Reporter Reporting Resistance Role Series Site Solid Neoplasm Testing Therapeutic Tumor Cell Line base cell killing chromatin immunoprecipitation design homologous recombination improved inhibitor/antagonist knock-down mouse model mutant neoplastic cell novel overexpression prevent radioresistant recombinational repair repaired tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Radiotherapy is a common cancer therapeutic approach but radioresistance in tumors frequently prevents successful cancer control; therefore, overcoming radioresistance is essential for improving radiotherapy. MicroRNA-21 (miR-21) is an onco-miR that over- expresses in almost all types of human tumors. We and others have demonstrated that over- expression of miR-21 could result in tumorigenesis. Currently, there are only a few reports showed that miR-21 contributes to radioresistance of tumor cells, and the mechanism remains unclear. Recently, by using our miR-21 knock-in or miR-21 knockout mouse models, the embryo fibroblast cells derived from the mouse strains and knocking down miR-21 in several human tumor cell lines, we found that miR-21 plays an important role in radioresistance that is involved in promoting DNA double strand break (DSB) repair. Based on our previous publications and preliminary data, we will test the hypothesis that miR-21-mediated radioresistance occurs through its targets to promote DNA DSB repair. Since IR-induced cell killing occurs mainly by generating DSBs, and non-homologous end joining (NHEJ) and homologous recombination repair (HRR) are the two major pathways in mammalian cells to repair DNA DSB, it is important to elucidate if miR-21-mediated radioresistance occurs through stimulating NHEJ, HRR or both. It is also important to elucidate how miR-21 affects the DNA repair pathway(s) via its targets including Pten and Cdc25A (known targets of miR-21), as well as GSK3b (a novel target of miR- 21 identified by our group). For this purpose, two aims are designed: 1) Determine if miR-21- mediated radioresistance occurs through stimulating NHEJ, HRR or both. 2) Determine how miR-21 mediates radioresistance through its targets. Since miR-21 over-expressed in almost all types of human tumors, the results from this proposal are expected to not only enhance our knowledge of tumor cell radioresistance, but also provide novel targets and pathways for improving tumor radiotherapy.

描述（由申请人提供）：放射治疗是一种常见的癌症治疗方法，但肿瘤的放射抗性经常阻碍癌症的成功控制；因此，克服放射抗性对于改善放射治疗至关重要。 MicroRNA-21 (miR-21) 是一种 onco-miR，在几乎所有类型的人类肿瘤中过度表达。我们和其他人已经证明 miR-21 的过度表达可能导致肿瘤发生。目前，只有少数报道表明miR-21有助于肿瘤细胞的放射抵抗，其机制尚不清楚。最近，通过使用我们的 miR-21 敲入或 miR-21 敲除小鼠模型，来自小鼠品系的胚胎成纤维细胞并敲低几个人类肿瘤细胞系中的 miR-21，我们发现 miR-21 在放射抗性中的作用涉及促进 DNA 双链断裂 (DSB) 修复。根据我们之前的出版物和初步数据，我们将检验以下假设：miR-21 介导的放射抗性通过其靶点发生，从而促进 DNA DSB 修复。由于IR诱导的细胞杀伤主要通过生成DSB发生，而非同源末端连接（NHEJ）和同源重组修复（HRR）是哺乳动物细胞修复DNA DSB的两条主要途径，因此阐明miR-21是否介导的放射抗性通过刺激 NHEJ、HRR 或两者而发生。阐明 miR-21 如何通过其靶标影响 DNA 修复途径也很重要，这些靶标包括 Pten 和 Cdc25A（miR-21 的已知靶标）以及 GSK3b（我们小组确定的 miR-21 的新靶标））。为此，设计了两个目标：1) 确定 miR-21 介导的放射抗性是否通过刺激 NHEJ、HRR 或两者而发生。 2) 确定 miR-21 如何通过其靶点介导放射抗性。由于miR-21在几乎所有类型的人类肿瘤中过度表达，该提案的结果预计不仅可以增强我们对肿瘤细胞放射抗性的认识，而且可以为改善肿瘤放疗提供新的靶点和途径。