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.

肺癌是美国癌症相关死亡的主要原因，每年约有 132,000 人死于肺癌 年。虽然肺腺癌的靶向治疗改善了总体生存率，但肺腺癌的类似进展 鳞状癌（LUSC）的发展一直停滞不前。通过癌症基因组进行广泛的分子分析 Atlas (TCGA) 工作表明，LUSC 肿瘤具有高度特殊性，很少由单独可操作的肿瘤驱动 途径。此外，大多数癌症相关死亡是由转移而非原发肿瘤造成的。 然而，人们对 LUSC 传播方式的机制基础知之甚少。在这个提案中，我们 将研究环状 RNA (circRNA) CDR1as 在调节 LUSC 转移中的作用。调查 为了了解 CDR1as 对 LUSC 转移的调节作用，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 数据与我们的小鼠整合 通过模型，我们发现 CDR1 是 LUSC 转移的关键驱动因素。我们发现CDR1as起着 在稳定小脑变性相关蛋白 1 (CDR1) 编码 mRNA 转录物方面发挥关键作用。我们发现 CDR1as 和 CDR1 对于 LUSC 转移都是必需的，并且仅 CDR1 过度表达就足够了 促进 LUSC 转移。我们发现 CDR1 与几种特定的高尔基体运输蛋白相互作用，并且 CDR1 表达与较差的 LUSC 存活率相对应，并与上皮间质转化紧密结合 （紧急医疗救护）计划。此外，我们还发现了 CDR1as 的关键结构元件，可促进其 RNA 稳定性 和表达水平。综上所述，出现了一些关键问题，例如：1）CDR1 在高尔基体中如何转运？ 囊泡促进迁移和转移？ 2) 寡核苷酸介导的CDR1as靶向能否阻断LUSC转移 并延长生存期？该提案的目标是定义 CDR1 如何促进 LUSC 转移 通过高尔基体贩运。我们还将确定中断结构的生物学和治疗意义 CDR1as 的元件。