Circle RNA Regulation of Lung Cancer Metastasis

Circle RNA对肺癌转移的调控

• 批准号: 10637900
• 负责人: Chad V Pecot
• 金额: $ 32.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-04 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637900
• 关键词: Accounting; Alternative Splicing; Antisense Oligonucleotides; Architecture; Bioinformatics; Biological; Cancer Etiology; Cancer Patient; Cerebellar Degeneration Related 1 Antisense; Cerebellar degeneration; Cessation of life; Chemicals; Clinical; Coat Protein Complex I; Code; Complex; Couples; Cues; Cytoskeleton; Data; Dependence; Electron Microscopy; Elements; Epithelium; Genetic Epistasis; Genetic Transcription; Golgi Apparatus; Immunohistochemistry; Interruption; Knock-out; Ligands; Light; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Mesenchymal; Messenger RNA; Methods; Microscopy; Modeling; Molecular Profiling; Mutate; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Nucleotides; Oligonucleotides; Outcome; Pathway interactions; Patients; Phenotype; Play; Primary Neoplasm; Proteins; RNA; RNA Stability; Regulation; Resolution; Role; Sampling; Site; Squamous Cell Lung Carcinoma; Structure; Survival Rate; Systemic Therapy; The Cancer Genome Atlas; Therapeutic; Untranslated RNA; Vesicle; anticancer research; chemotherapy; experimental study; genetic approach; human disease; improved; insight; migration; mouse model; novel therapeutics; overexpression; programs; protein transport; spatial relationship; stem; targeted treatment; trafficking; tumor; tumorigenic; vesicle transport

Lung cancer is the leading cause of cancer-related deaths in the U.S., accounting for about 132,000 deaths per year. While targeted therapies of lung adenocarcinoma have improved overall survival, similar advances in lung squamous carcinoma (LUSC) have been stagnant. Extensive molecular profiling through the Cancer Genome Atlas (TCGA) effort revealed that LUSC tumors are highly idiosyncratic and rarely driven by solitary actionable pathways. Also, metastasis, rather than primary tumors, is responsible for the majority of cancer-related deaths. However, the mechanistic underpinnings of how LUSC spreads are very poorly understood. In this proposal, we will investigate the roles of a circle RNA (circRNA), CDR1as, on its regulation of LUSC metastasis. To investigate the regulatory role of CDR1as on LUSC metastasis, we have recently developed sophisticated LUSC models that metastasize to sites common to human disease. By integrating clinical LUSC TCGA data with our mouse models, we have identified CDR1as as a key driver of LUSC metastasis. We have found that CDR1as plays a key role in stabilizing the coding mRNA transcript for cerebellar degeneration-related protein 1 (CDR1). We found that CDR1as and CDR1 are each necessary for LUSC metastasis, and CDR1 over-expression alone is sufficient to promote LUSC metastasis. We found CDR1 interacts with several specific Golgi trafficking proteins, and CDR1 expression corresponds with poor LUSC survival and tightly couples with an epithelial-mesenchymal transition (EMT) program. Additionally, we have found key structural elements of CDR1as that promote its RNA stability and expression levels. Taken together, key questions arise, such as: 1) How does CDR1 trafficking in the Golgi vesicles promote migration and metastasis? 2) Can oligo-mediated targeting of CDR1as block LUSC metastasis and prolong survival? The objectives of this proposal are to define how CDR1 promotes LUSC metastasis through Golgi trafficking. We will also determine the biologic and therapeutic implications of interrupting structural elements of CDR1as.

肺癌是美国与癌症相关死亡的主要原因，约占132,000人死亡 年。虽然针对肺腺癌的靶向疗法提高了总体生存率，但肺部的进展相似 鳞状癌（LUSC）停滞不前。通过癌症基因组进行广泛的分子分析 Atlas（TCGA）的努力表明，LUSC肿瘤是高度特质的，很少受到孤立驱动的驱动 途径。同样，转移而不是原发性肿瘤是造成大多数与癌症相关的死亡的原因。 但是，LUSC传播方式的机械基础知之甚少。在这个建议中，我们 将研究圆圈RNA（circRNA），CDR1AS对LUSC转移的调节的作用。调查 CDR1AS在LUSC转移中的调节作用，我们最近开发了复杂的LUSC模型 转移到人类疾病常见的部位。通过将临床LUSC TCGA数据与我们的鼠标集成 模型，我们将CDR1AS确定为LUSC转移的关键驱动力。我们发现CDR1A扮演 在稳定小脑变性相关蛋白1（CDR1）的编码mRNA转录本方面的关键作用。我们发现 CDR1A和CDR1对于LUSC转移都是必需的，仅CDR1过表达就足够了 促进LUSC转移。我们发现CDR1与几种特定的高尔基运输蛋白相互作用，而CDR1 表达与LUSC生存不良，并与上皮间质转变紧密伴侣 （EMT）程序。此外，我们发现CDR1A的关键结构元素促进其RNA稳定性 和表达水平。综上 囊泡促进迁移和转移？ 2）寡核介导的CDR1AS块块lusc转移的靶向 延长生存？该提案的目标是定义CDR1如何促进LUSC转移 通过高尔基人贩运。我们还将确定中断结构的生物学和治疗意义 CDR1A的元素。