Induction of Tumor Cell Dormancy by Ribosomal Intergenic Spacer Noncoding RNA

核糖体基因间间隔区非编码 RNA 诱导肿瘤细胞休眠

• 批准号: 9186532
• 负责人: Stephen Lee
• 金额: $ 35.11万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186532
• 关键词: Acidosis; Antimitotic Agents; Antineoplastic Agents; Applications Grants; Biochemical; Biological; Biology; Cell Cycle; Cell Nucleolus; Cell Survival; Cell physiology; Cells; Cellular Stress Response; Common Neoplasm; Cues; DNA biosynthesis; Data; Disease; Doxorubicin; Elements; Evolution; Excision; Exposure to; Genetic Transcription; Human; Human Genome; Hyperthermia; Immobilization; Investigation; Life; Malignant Neoplasms; Maps; Mediating; Metabolism; Molecular; Nature; Neoplasm Metastasis; Nucleolar Proteins; Paper; Pathway interactions; Phenotype; Physiological; Play; Population Heterogeneity; Primary Neoplasm; Prisons; Proteins; Proteome; Proteomics; RNA; Recombinant DNA; Recurrence; Regulatory Pathway; Reporting; Resistance; Resistance Process; Ribosomes; Role; Scientist; Stimulus; Stress; Surveys; Testing; Therapeutic; Translations; Untranslated RNA; Work; anti-cancer therapeutic; base; cancer cell; cancer therapy; detention center; extracellular; fascinate; innovation; interest; metabolic abnormality assessment; neoplastic cell; protein function; public health relevance; response; stressor; tumor; tumor microenvironment; tumorigenesis

 DESCRIPTION (provided by applicant): The ability of cancer cells to adapt to a wide variety of stress conditions plays a critical role in various physiological facets of tumorigenesis. We recently reported the discovery of a class of stress-induced long noncoding RNAs derived from stimuli-specific loci of the ribosomal intergenic spacer (Mol. Cell (2012) 45:147), a puzzling region of the human genome historically assumed to be transcriptionally inactive. Induction of rDNA intergenic spacer RNA (IGSRNA) converts the nucleolus from a factory of ribosomes to the Nucleolar Detention Center: a molecular prison that immobilizes specific proteins in response to extracellular stressors (Nature Cell Biol. (2004) 6:642; J.Cell. Biol. (2005) 170:733; Mol. Biol. Cell. (2013) 24: 2943). The Nucleolar Detention Center is observed in cells that populate the core of human tumors and is induced by various cancer-related stressors, including extracellular acidosis and the anti-mitotic therapeutic doxorubicin. We will show preliminary data that the Nucleolar Detention Center comprises of a biochemically heterogeneous population of proteins including elements of the DNA synthesis machinery. Cancer cells activate IGSRNA- mediated nucleolar immobilization of proteins to reduce metabolism and withdraw from the cell cycle in an adaptive response to severe environmental insults. This raises the fascinating possibility that the IGSRNA are involved in the attainment of tumor cell dormancy, a critical phenotype in a cancer cell's ability to sustain viability in the hash conditions of the tumor microenvironment and resist anti-cancer therapy. Based on these aforementioned rationales, we propose the following hypothesis: Stimuli-specific formation of the Nucleolar Detention Center by IGSRNA induces tumor cell dormancy. In the Specific Aims, we will: 1- Survey the ribosomal intergenic spacer for IGSRNA induced by cancer-related stressors; 2- Examine the specific Nucleolar Detention Center proteomes as a function of various stress conditions; 3- Demonstrate a role for the IGSRNA-mediated Nucleolar Detention Center in the dormant tumor cell phenotype. The discovery of the IGSRNA-regulated Nucleolar Detention Center constitutes a unique and remarkable window of opportunity to investigate a largely unexplored post-translational mechanism potentially involved in tumor cell dormancy. These studies will yield significant conceptual advances in our understanding of critical adaptive/resistance processes exploited by cancer cells to sustain viability in the tumor microenvironment and resistance to anti- cancer drugs.

 描述（由申请人提供）：癌细胞适应各种应激条件的能力在肿瘤发生的各种生理学方面起着关键作用。我们最近报道了一类应激诱导的长非编码RNA的发现，这些长非编码RNA来源于核糖体基因间间隔区（Mol. Cell（2012）45：147），这是人类基因组中一个令人困惑的区域，历史上被认为是转录失活的。rDNA基因间间隔区RNA（IGSRNA）的诱导将核仁从核糖体工厂转化为核仁滞留中心（Nucleolar Detention Center）：响应于细胞外应激物而固定特定蛋白质的分子监狱（Nature Cell Biol.（2004）6：642; J.Cell.（2005）170：733; Mol.生物细胞（2013）24：2943）。核仁滞留中心在人类肿瘤核心的细胞中观察到，并由各种癌症相关的应激源诱导，包括细胞外酸中毒和抗有丝分裂治疗药物阿霉素。我们将展示的初步数据表明，核仁滞留中心包括一个生物化学异质性人口的蛋白质，包括元素的DNA合成机制。癌细胞激活IGSRNA介导的蛋白质的核仁固定以减少代谢并在对严重环境损伤的适应性反应中退出细胞周期。这提出了IGSRNA参与实现肿瘤细胞休眠的迷人可能性，这是癌细胞在肿瘤微环境的散列条件下维持生存能力和抵抗抗癌治疗的关键表型。基于上述理论，我们提出了以下假设：IGSRNA刺激特异性形成的核仁滞留中心诱导肿瘤细胞休眠。在具体的目标，我们将：1-调查核糖体基因间间隔的IGSRNA诱导癌症相关的压力; 2-检查特定的核仁滞留中心蛋白质组作为各种压力条件的功能; 3-证明IGSRNA介导的核仁滞留中心在休眠肿瘤细胞表型中的作用。IGSRNA调节的核仁滞留中心的发现构成了一个独特而显着的机会窗口，以调查可能涉及肿瘤细胞休眠的大量未探索的翻译后机制。这些研究将在我们对癌细胞利用关键适应/抗性过程的理解中产生重大的概念性进展，以维持肿瘤微环境中的活力和对抗癌药物的抗性。