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13.2万人死于肺癌