New perspective on MyoD function and differentiation in rhabdomyosarcoma

横纹肌肉瘤中MyoD功能和分化的新视角

基本信息

批准号：
10532209
负责人：
Denis C Guttridge
金额：
$ 34.64万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532209
关键词：
Acute Promyelocytic Leukemia Adolescent Apoptosis Binding Binding Proteins Binding Sites Cell Death Cell Differentiation process Cell Line Cell Survival Cells ChIP-seq Chemoresistance Child Chromatin Combined Modality Therapy Complex Data Data Set Diagnosis Differentiation Inhibitor Disease E2F transcription factor 6 protein Epithelium Failure Functional disorder Future Genes Genetic Transcription Goals Histologic HuR protein Informatics Laboratories Link Malignant Childhood Neoplasm Malignant Neoplasms Mediating Messenger RNA MicroRNAs Mus Muscle MyoD Protein Myogenin Pathogenesis Patients Phenotype Play Property Refractory Regulation Repressor Proteins Resistance Rhabdomyosarcoma Role Signal Pathway Skeletal Muscle Soft tissue sarcoma Stress Survival Rate Testing Tissues Tretinoin Tumor Suppressor Proteins United States Work YY1 Transcription Factor cancer cell cell growth chemotherapy effective therapy functional disability gene repression genetic corepressor insight interest myogenesis neoplastic cell novel prevent promoter skeletal skeletal muscle differentiation soft tissue stemness therapeutically effective transcription factor tumor tumor progression tumorigenic young adult

项目摘要

ABSTRACT Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents in the United States. While generally very treatable, advanced RMS often proves resistant to treatment and results in poor survival. RMS is linked to a muscle lineage and is believed to result, at least in part, from a failure of the transcription factor MyoD to functionally promote terminal differentiation. Our laboratory has long studied the role of NF-κB as a regulator of skeletal muscle differentiation, and has shown that active NF-κB prevents the maturation of muscle, which is relevant in a number of diseases, including RMS. Because NF-κB is known to play an important role in the ability of a number of cancers to resist cell death, we examined whether NF-κB would have the same cell survival activity in RMS cells as a potential mechanism of chemoresistance. Interestingly, RMS cells depleted of NF-κB remained resistant to stress. This finding led us to uncover that RMS cells depend upon MyoD for cell survival. Further, we have determined that this MyoD-mediated resistance to cell death occurs through a novel transcriptional repressive function of MyoD. The goal of our project is to explore a potential new function of MyoD as a cell survival factor in the progression of RMS and unravel the manner in which MyoD is acting to repress gene transcription, potentially relevant to RMS pathogenesis. Because the current paradigm of future RMS treatments is to promote cell differentiation through stimulation of MyoD, our current findings paired with our proposed aims have the potential to alter future RMS therapies. !

抽象的横纹肌肉瘤（RMS）是美国儿童和青少年最常见的软组织肉瘤国家。虽然通常非常可以治疗，但晚期RMS通常证明对治疗有抵抗力，并导致差生存。 RMS与肌肉谱系有关，据信至少部分是由于转录因子myod在功能上促进末端分化。我们的实验室长期研究了 NF-κB作为骨骼肌分化的调节剂的作用，并表明活跃的NF-κB阻止了肌肉的成熟，这与包括RMS在内的多种疾病有关。因为已知NF-κB 在许多癌症抵抗细胞死亡的能力中起着重要作用，我们检查了NF-κB是否在RMS细胞中，将具有相同的细胞存活活性，作为化学抗性的潜在机制。有趣的是，耗尽NF-κB的RMS细胞对应力仍然具有抵抗力。这一发现使我们发现了 RMS细胞依靠Myod来存活。此外，我们已经确定了这个myod介导的对细胞死亡的抗性是通过MYOD的新型转录反射功能发生的。我们的目标项目是探索MYOD作为RMS和RMS进展中细胞存活因子的潜在新功能揭示Myod的作用方式反映基因转录的方式，可能与RMS有关发病。因为未来RMS处理的当前范式是促进细胞分化通过刺激Myod，我们目前的发现与我们提出的目标配对有可能改变未来的RMS疗法。呢