Mechanisms of lincDUSP Oncogenic Effects in Colon Cancer

lincDUSP 对结肠癌的致癌作用机制

• 批准号: 10232150
• 负责人: Thomas Louis LaFramboise
• 金额: $ 36.09万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10232150
• 关键词: 3-Dimensional; Affect; Apoptosis; Automobile Driving; Biological Markers; Cancer Etiology; Cells; Cessation of life; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Colon; Colon Carcinoma; Colonic Neoplasms; Complex; DNA; Data; Disease; Epithelial; Gene Expression; Gene Expression Regulation; Genes; Genomics; Goals; Health; Human; Immunodeficient Mouse; KRAS2 gene; Knock-out; Laboratories; Lead; MADH4 gene; Malignant Neoplasms; Mediating; Molecular; Mutation; NMR Spectroscopy; Nuclear; Oncogenes; Oncogenic; Organoids; Patients; Phenotype; Play; Process; Proteins; RNA; RNA Binding; RNA analysis; Recurrence; Role; Site; Structure; TP53 gene; Testing; The Cancer Genome Atlas; Tissues; Treatment Failure; Tumor Cell Line; United States; Untranslated RNA; Up-Regulation; Validation; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cancer type; chromatin isolation by RNA purification sequencing; cohort; colon cancer cell line; colon tumorigenesis; experimental study; genome-wide; genomic locus; in vivo; knock-down; new therapeutic target; novel; novel therapeutics; overexpression; protein complex; recruit; targeted treatment; transcriptome sequencing; tumor; tumor microenvironment

PI: Khalil, Ahmad Technical Abstract: Colon cancer is the second leading cause of cancer-related death in the United States, largely due to frequent treatment failure and recurrence. Recent studies, including work from our laboratory, have demonstrated that regulatory long intergenic non-coding RNAs (lincRNAs) are major players in the process of colon tumorigenesis, and could emerge as novel therapeutic targets. In this proposal, we have identified and functionally characterized a novel lincRNA, referred to as lincDUSP, that exerts an oncogenic effect in colon cancer cells. Knockdown of lincDUSP significantly abrogates the tumor phenotype, including decreased proliferation and colony formation, and increased apoptosis. These studies have also revealed that lincDUSP regulates numerous genes by directly interacting with chromatin, and potentially recruiting protein complexes to specific genomic loci. In aim 1 of this proposal, we will further test the oncogenic function of lincDUSP in vivo using a xenograft model, and also assess the role of lincDUSP in driving colon tumorigenesis using 3D organoids. In aim 2, we will investigate the molecular mechanisms of lincDUSP by assessing its role in gene regulation, and characterize the protein complexes that are required for lincDUSP oncogenic activity. Lastly, we will determine the secondary structure of lincDUSP that facilitates its interaction with DNA and proteins. The completion of the proposed studies could lead to establishing lincDUSP as a novel oncogenic lincRNA with direct impact on colon tumorigenesis, and possibly as a target for therapy.

PI：Khalil，Ahmad 技术摘要： 结肠癌是美国癌症相关死亡的第二大原因， 由于频繁的治疗失败和复发。最近的研究，包括我们的工作， 实验室，已经证明了调节性长基因间非编码RNA（lincRNA）是 结肠肿瘤发生过程中的主要参与者，并可能成为新的治疗方法 目标的在这项提议中，我们已经鉴定并功能性地表征了一种新的lincRNA， 称为lincDUSP，其在结肠癌细胞中发挥致癌作用。敲低 lincDUSP显著消除肿瘤表型，包括增殖减少， 集落形成和凋亡增加。这些研究还表明，lincDUSP 通过直接与染色质相互作用调节许多基因， 蛋白质复合物与特定的基因组位点。在本提案的目标1中，我们将进一步测试 使用异种移植模型在体内评估lincDUSP的致癌功能，并且还评估lincDUSP的作用。 lincDUSP使用3D类器官驱动结肠肿瘤发生。在目标2中，我们将研究 lincDUSP的分子机制，通过评估其在基因调控中的作用，并表征 lincDUSP致癌活性所需的蛋白质复合物。最后，我们将 确定促进其与DNA相互作用的lincDUSP的二级结构， proteins.完成拟议的研究可能会导致建立lincDUSP作为一种新的 致癌lincRNA对结肠肿瘤发生有直接影响，并可能作为靶点， 疗法