Induction of Tumor Cell Dormancy by Ribosomal Intergenic Spacer Noncoding RNA

 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个生理方面发挥着关键作用。我们最近报道了一类由核糖体基因间隔区(MOL)的刺激性位点产生的应激诱导的长非编码RNA的发现。Cell(2012)45：147)，这是人类基因组中一个令人费解的区域，历史上认为它在转录上不活跃。RDNA基因间隔区RNA(IGSRNA)的诱导将核仁从核糖体工厂转换到核仁滞留中心：一个使特定蛋白质固定以应对细胞外应激源的分子监狱(自然细胞生物)。(2004)6：642；J.Cell.比奥尔。(2005)170：733；莫尔比奥尔。牢房。(2013)24：2943)。核仁滞留中心存在于人类肿瘤核心的细胞中，由多种癌症相关应激源诱导，包括细胞外酸中毒和抗有丝分裂治疗阿霉素。我们将展示初步数据，核仁滞留中心由生化上不同种类的蛋白质组成，其中包括DNA合成机制的元素。癌细胞激活IGSRNA介导的核仁蛋白质固定化，以减少新陈代谢并退出细胞周期，以适应严重的环境侮辱。这提出了一种有趣的可能性，即IGSRNA参与了肿瘤细胞休眠的实现，这是癌细胞在肿瘤微环境的杂乱条件下维持生存和抵抗抗癌治疗能力的关键表型。基于上述原理，我们提出了以下假设：IGSRNA刺激特异性地形成核仁滞留中心可诱导肿瘤细胞休眠。在特定的目标中，我们将：1-调查癌症相关应激源诱导的IGSRNA的核糖体基因间隔区；2-检测特定的核仁滞留中心蛋白质组作为各种应激条件的函数；3-展示IGSRNA介导的核仁滞留中心在休眠肿瘤细胞表型中的作用。IGSRNA调控的核仁滞留中心的发现构成了一个独特而非凡的机会之窗，以研究一种在很大程度上未被探索的潜在参与肿瘤细胞休眠的翻译后机制。这些研究将在我们理解癌细胞用来维持肿瘤微环境中的生存能力和抗癌药物耐药性的关键适应/耐药过程方面取得重大的概念性进展。

 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.