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

• 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
• 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

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. !

摘要 横纹肌肉瘤(RMS)是美国儿童和青少年最常见的软组织肉瘤 各州。虽然通常非常可治疗，但晚期RMS通常被证明对治疗耐药，结果很差。 生死存亡。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。我们的实验室长期以来一直在研究 核因子-κB作为骨骼肌分化调节因子的作用，并已表明活性的核因子-κB阻止 肌肉的成熟，这与包括RMS在内的许多疾病有关。因为已知核因子-κB 在许多癌症抵抗细胞死亡的能力中发挥重要作用，我们检查了NF-κB 在RMS细胞中具有相同的细胞存活活性，作为一种潜在的化疗耐药机制。 有趣的是，缺失了核因子-κB的RMS细胞仍然对应激具有抵抗力。这一发现使我们发现了 RMS细胞依赖MyoD维持细胞生存。此外，我们已经确定这一MyoD介导的 对细胞死亡的抵抗是通过MyoD的一种新的转录抑制功能发生的。我们的目标是 项目是探索MyoD作为细胞生存因子在RMS和RMS进展中的潜在新功能 解开MyoD抑制基因转录的方式，这可能与RMS有关 发病机制。因为未来RMS治疗的当前模式是促进细胞分化 通过对MyoD的刺激，我们目前的发现与我们提出的目标相结合，有可能改变 未来的RMS疗法。 好了！