Epigenetic modulation of lung cancer metastasis by a novel long intergenic RNA

新型长基因间RNA对肺癌转移的表观遗传调节

• 批准号: 8900254
• 负责人: Don X Nguyen
• 金额: $ 18.11万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900254
• 关键词: Accounting; Acute; Adenocarcinoma Cell; Affect; Biochemical; Biological; Biological Assay; Biological Markers; Biological Process; Cancer Patient; Cell Differentiation process; Cell model; Cell physiology; Cells; Cessation of life; Clinical; Clinical Trials; Code; Collaborations; Colorectal Cancer; Competence; Complex; Data; Disease; Distant; Enzymes; Epigenetic Process; Event; Experimental Models; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Heterogeneity; Genetic Transcription; Genomics; Goals; Health; Human; Human Genome; In Situ; In Vitro; Indolent; Light; Link; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Malignant neoplasm of thorax; Maps; Mediating; Mediator of activation protein; Medicine; Metastasis Suppressor Genes; Molecular; Neoplasm Metastasis; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Polycomb; Primates; Probability; Process; Protein Subunits; Proteins; RNA; RNA Sequence Analysis; RNA Sequences; Reading; Relapse; Repression; Risk; Role; Somatic Mutation; Source; Stratification; System; Techniques; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Transcript; Tumor Cell Invasion; Tumor Tissue; Untranslated RNA; X Chromosome; Xenograft Model; base; cancer cell; chromatin remodeling; epigenetic marker; gene repression; histone methyltransferase; in vivo Model; inhibitor/antagonist; innovation; insight; loss of function; malignant breast neoplasm; neoplastic cell; novel; programs; promoter; protein complex; research study; small hairpin RNA; small molecule; therapeutic target; transcriptome sequencing; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Thoracic malignancies account for more deaths than prostate, breast and colorectal cancer combined. The most frequent lung cancer subtype is lung adenocarcinoma (LUAD), which is initiated in the peripheral airways and can disseminate rapidly to other vital organs. There are currently no effective therapeutics for metastatic LUAD, which are biologically and genetically diverse. In addition, recent genomic re-sequencing efforts have revealed thousands of new human gene loci that, despite not coding for any proteins, may be critical to human medicine. Given the heterogeneity and genetic complexity of LUADs, a multi-disciplinary approach is needed to understand the molecular pathogenesis of lung cancer metastasis and uncover novel mediators and biomarkers of this disease. Through computational and experimental approaches, we examined the molecular relationship between cell differentiation states, lung cancer subtypes, and clinical outcome, to discover a role for cel lineage- restricted genes in metastatic LUAD. These alterations include changes in the transcription of novel long intergenic non-coding RNAs (lincRNAs) with unknown function. In particular, we identified one lincRNA, referred to here as linc-XIM (X-linked inhibitor of metastasis), as a potential suppressor of metastasis and biomarker of epigenetic abnormalities specifically in human LUADs. We posit that linc-XIM inhibits metastasis by antagonizing the activity of the Polycomb repressor complex 2 (PRC2) and/or its recruitment to relevant genomic targets. Thus, repression of linc-XIM may enhance metastatic competence of LUADs by epigenetically reprogramming the transcriptome of indolent LUAD cells. We will test this hypothesis by first characterizing the biological function(s) of linc-XIM during lung LUAD differentiation, tumor growth and distant organ metastasis, using our established in vivo model of metastatic dissemination and colonization by human LUAD cells. We will employ genetic and pharmacological approaches that enable temporally controlled gain and loss of function, to establish the functional association between linc-XIM expression and PRC2 activity. In parallel to these biological experiments, we will combine molecular, biochemical, and in situ techniques to elucidate the mechanism by which linc-XIM sequesters or inhibits PRC2 protein subunits and ultimately regulates epigenetic silencing. Finally, we will examine the correlation between the expression of linc-XIM, PRC2 subunits, PRC2 target genes, and clinical outcome in human LUAD biospecimens. The overall goal of our application may therefore shed new light into the role of tissue specific lincRNAs in cancer progression, and provide insights into more effective epigenetic therapies for lung cancer patients at risk for metastatic disease.

描述（由申请人提供）：胸部恶性肿瘤造成的死亡人数比前列腺癌、乳腺癌和结直肠癌的总和还多。最常见的肺癌亚型是肺腺癌（LUAD），它起源于外周气道，可以迅速扩散到其他重要器官。目前尚无针对转移性 LUAD 的有效治疗方法，其在生物学和遗传上具有多样性。此外，最近的基因组重测序工作揭示了数千个新的人类基因位点，尽管它们不编码任何蛋白质，但可能对人类医学至关重要。鉴于 LUAD 的异质性和遗传复杂性，需要采用多学科方法来了解肺癌转移的分子发病机制，并发现该疾病的新介质和生物标志物。 通过计算和实验方法，我们检查了细胞分化状态、肺癌亚型和临床结果之间的分子关系，以发现细胞谱系限制基因在转移性 LUAD 中的作用。这些改变包括功能未知的新型长基因间非编码 RNA (lincRNA) 转录的变化。特别是，我们鉴定了一种 lincRNA，这里称为 linc-XIM（X 连锁转移抑制剂），作为潜在的转移抑制剂和表观遗传异常的生物标志物，特别是在人类 LUAD 中。我们假设 linc-XIM 通过拮抗 Polycomb 阻遏物复合物 2 (PRC2) 的活性和/或其招募到相关基因组靶标来抑制转移。因此，抑制 linc-XIM 可能通过对惰性 LUAD 细胞的转录组进行表观遗传重编程来增强 LUAD 的转移能力。 我们将通过首先使用我们建立的人 LUAD 细胞转移传播和定植的体内模型来表征 linc-XIM 在肺 LUAD 分化、肿瘤生长和远处器官转移过程中的生物学功能来检验这一假设。我们将采用遗传和药理学方法来暂时控制功能的获得和丧失，以建立 linc-XIM 表达和 PRC2 活性之间的功能关联。在这些生物学实验的同时，我们将结合分子、生化和原位技术来阐明 linc-XIM 隔离或抑制 PRC2 蛋白亚基并最终调节表观遗传沉默的机制。最后，我们将检查人类 LUAD 生物样本中 linc-XIM、PRC2 亚基、PRC2 靶基因的表达与临床结果之间的相关性。因此，我们应用的总体目标可能为了解组织特异性 lincRNA 在癌症进展中的作用提供新的线索，并为有转移性疾病风险的肺癌患者提供更有效的表观遗传疗法。