The epigenetic mechanism of long non-coding RNA in cancer

长链非编码RNA在癌症中的表观遗传机制

基本信息

批准号：
8797489
负责人：
Lin Zhang
金额：
$ 36.6万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-06 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8797489
关键词：
B-Cell Lymphomas BMI1 gene Biochemical Biological Markers CDKN1A gene Cancer cell line Cell physiology Cells ChIP-seq Chromatin Code Complex Core Protein DNA Sequence Alteration Data Disease Epigenetic Process Epithelial Exhibits Figs - dietary Gene Expression Regulation Genes Genetic Screening Genetic Transcription Genome Guide RNA Hereditary Disease Homologous Gene Human Human Genome Informatics Investigation Laboratories Lead Libraries Malignant - descriptor Malignant Neoplasms MicroRNAs Modeling Molecular Nature Neoplasm Metastasis Oncogenic Outcome PRC1 Protein Pathology Pathway interactions Patients Process Proteins RNA RNA Binding RNA-Protein Interaction Recruitment Activity Regulation Reporting Repression Research Resources Ribonucleoproteins Role Small Interfering RNA Specimen System Technology Testing The Cancer Genome Atlas Transcript Transgenic Mice Untranslated RNA Xenograft Model base cancer cell cancer genome cancer initiation cancer type clinical application in vivo infancy mouse model new therapeutic target novel oncology public health relevance scaffold screening senescence therapeutic target transcriptome sequencing tumor tumor growth tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): Cancer is a genetic disease involving multi-step changes in the genome. The human genome contains ~25,000 protein-coding genes, representing less than 2% of the total genome, whereas up to 70% of the human genome is transcribed into RNA, yielding many thousands of non-coding RNAs. The recent discovery of non-coding RNAs, including small non-coding RNAs such as microRNA, has dramatically altered our understanding of cancer. However, research on long non-coding transcripts is still in its infancy. Long non-coding RNAs (lncRNAs) are operationally defined as RNA transcripts larger than 200 nt that do not appear to have protein-coding potential. Rapidly accumulating evidence indicates that lncRNA is involved in the initiation and progression of cancer. A novel oncogenic lncRNA, FAL1 (Focal Amplified lncRNA 1), has recently been identified by the PI's laboratory. Our preliminary data indicate that: amplification and high expression of FAL1 are correlated with poorer outcomes in cancer; FAL1 RNA associates with the epigenetic repressor BMI1, regulating its stability; knockdown of FAL1 increases the transcription of a number of genes, including CDKN1A; the oncogenicity of FAL1 is partially attributable to its repression of p21 expression; and FAL1-specific small interfering RNAs significantly inhibit tumor growth in vivo. Therefore, we hypothesize that the novel oncogenic lncRNA FAL1 epigenetically regulates multiple cancer-associated pathways via its interaction with BMI1, and that the investigation of the function of FAL1 may provide novel biomarkers and therapeutic targets for patients with cancer. We will test this hypothesis through the following specific aims: Specific Aim 1. Characterize the molecular mechanisms by which FAL1 regulates BMI1 stability. Specific Aim 2. Identify the molecular network epigenetically regulated by FAL1/BMI1 in cancer cells. Specific Aim 3. Examine the cellular functions of FAL1 in cancer initiation and progression.

描述（由申请人提供）：癌症是一种遗传疾病，涉及基因组的多步变化。人基因组包含约25,000个蛋白质编码基因，占总基因组的不到2％，而多达70％的人基因组被转录为RNA，产生了数千个非编码RNA。最近发现的非编码RNA，包括小型非编码RNA，例如microRNA，已极大地改变了我们对癌症的理解。但是，对长期非编码转录本的研究仍处于起步阶段。长的非编码RNA（LNCRNA）在操作上定义为大于200 nt的RNA转录本，似乎没有蛋白质编码的势。迅速积累的证据表明lncRNA参与癌症的起始和进展。 PI的实验室最近发现了一种新型的致癌LNCRNA FAL1（局灶性扩增的LNCRNA 1）。我们的初步数据表明：FAL1的扩增和高表达与癌症的较差相关； FAL1 RNA与表观遗传阻遏物BMI1相关，从而调节其稳定性； FAL1的敲低增加了包括CDKN1A在内的许多基因的转录； FAL1的致癌性部分归因于其对P21表达的抑制。 FAL1特异性干扰RNA显着抑制体内肿瘤的生长。因此，我们假设新型致癌性LNCRNA FAL1通过与BMI1的相互作用表观遗传遗传来调节多个癌症相关的途径，并且对FAL1功能的研究可能为患有癌症患者提供新颖的生物标志物和治疗靶标。我们将通过以下特定目的检验该假设：特定目的1。表征FAL1调节BMI1稳定性的分子机制。具体目标2。鉴定癌细胞中由FAL1/BMI1表观遗传调节的分子网络。具体目标3。检查FAL1在癌症开始和进展中的细胞功能。