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MicroRNA Biogenesis and the Cancer Proteome

MicroRNA 生物发生和癌症蛋白质组

基本信息

批准号：
7431456
负责人：
MARK D JOHNSON
金额：
$ 262.5万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7431456
关键词：
Accounting Acids Actins Address Affect Affinity Agreement Algorithms Anabolism Anecdotes Animals Apoptosis Area Attention Award Behavior Bibliography Binding Biogenesis Bioinformatics Biological Biological Assay Biological Process Biomedical Computing Biostatistical Methods Biotin Brain Brain Glioblastoma Brain Neoplasms Breast Camptothecin Cancer Biology Cancer Model Cancer Patient Cancer Survivorship Caring Caspase Categories Cations Cell Cycle Cell Cycle Progression Cell Death Cell Differentiation process Cell Line Cell Proliferation Cells Cellular Assay Cellular biology Cessation of life Characteristics Chemicals Chromatography Chromosome Pairing Cleaved cell Clinic Clinical Clinical Data Clinical Research Cluster Analysis Code Collaborations Color Complex Computer software Computers Condition Control Animal Core Facility Coupled Creativeness Cyclic AMP-Dependent Protein Kinases Cyclin-Dependent Kinases Cyclotrons DICER1 gene DNA DNA Damage DNA Integration DNA Sequence DNA analysis Data Data Analyses Data Set Defect Development Disease regression Disruption Distress Doctor of Philosophy Down-Regulation Dyes Elements Embryo Exhibits Failure Family Figs - dietary Fostering Fourier Transform Freezing Frequencies Functional RNA Gene Cluster Gene Expression Gene Mutation Gene Order Genes Genetic Genets Genome Genome Mappings Genomics Glioblastoma Glioma Glutamates Growth Guidelines HDAC1 gene Hematoxylin and Eosin Staining Method Heterogeneity Histology Hospital Records Hospitals Human Human Resources Immigration Implant In Vitro Individual Institution Ions Isotopes Isotopically-Coded Affinity Tagging Journals Kolmogorov-Smirnov Test Label Laboratories Lead Light Liquid Chromatography Location Lung Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of lung Manuscripts Mass Spectrum Analysis Measurement Measures Mediating Mentors Messenger RNA Metabolic Methodology Methods Methylation MicroRNAs Microarray Analysis Mitogens Modeling Molecular Molecular Profiling Molecular and Cellular Biology Mus Mutation National Cancer Institute Nature Nervous system structure Neurobiology Neurons Neurosurgeon Normal Cell Numbers Oncogenes Operative Surgical Procedures Outcome Output Ovarian PDGFRA gene Paper Pathway Analysis Pathway interactions Patients Pattern Peptides Physical Map of the Human Genome Play Polymerase Chain Reaction Positioning Attribute Primary Neoplasm Probability Process Production Protein Overexpression Proteins Proteome Proteomics Protocols documentation Publishing RLK5-associated protein phosphatase RNA RNA Polymerase III RNA Splicing RNA analysis Range Rate Rattus Recording of previous events Regression Analysis Regulation Relative (related person)Reporting Research Research Ethics Committees Research Personnel Residencies Resolution Resources Role Sampling Scanning Science Scientist Seminal Signal Pathway Signal Transduction Skin Slide Solid Source Specificity Specimen Spottings Staging Students Subfamily lentivirinae Subgroup Survival Analysis Synapses System TP53 gene Techniques Technology Testing Time Tissue Banks Tissue Extracts Tissue Sample Tissues Training Translational Research Translations Trypsin Tumor Suppressor Proteins Tumor Tissue Tumorigenicity Universities Up-Regulation Validation Washington Week Western Blotting Width Woman Work abstracting animal care base cancer cell cancer genome carcinogenesis career cell growth cell motility cellular transduction clinically relevant comparative cyanine dye 5 cyclin-dependent kinase 6 density fight against follow-up forging frontier functional genomics genome-wide analysis hazard human DICER1 protein human subject improved in vitro Assay in vitro Model in vivo innovation insight interest mRNA Expression mRNA Stability mass spectrometer medical schools member metaplastic cell transformation mouse model neoplastic cell neuron apoptosis neuron loss neurosurgery novel novel therapeutics outcome forecast peripheral blood physical mapping postnatal programs protein expression research study response reversed phase chromatography size small hairpin RNA statistics success synthetic protein therapeutic target therapy outcome tool tumor tumorigenesis vector vector control willingness

项目摘要

Recent studies in human cancers have revealed defects in microRNA biogenesis that promote tumor aggressiveness and decrease survival via mechanisms that are poorly understood. Much of the control of protein expression by microRNAs occurs without alterations in mRNA expression, and single microRNAs may target dozens of mRNAs in a tissue specific manner. Thus, this broad-based decrease in microRNA synthesis presents a challenge to those trying to understand its downstream molecular effects on carcinogenesis. Here we propose a new strategy that will comprehensively identify the mechanisms by which defects in microRNA biogenesis decrease cancer survivorship. This approach involves the integration of genome-scale high throughput quantitative mass spectrometry analysis of the cancer proteome with genome-wide microRNA, mRNA and DNA analyses of human brain tumors (glioblastomas) that have intact or defective microRNA biogenesis. Novel algorithms that incorporate clinical variables will be used to generate an integrated genome- scale view of identified differences, and clinically-related targets will be investigated further using in vivo and in vitro models. Preliminary studies in our laboratory using aCGH and mRNA microarrays revealed deletion at the DICER1 locus and decreased DICER1 mRNA expression in a subset of glioblastomas, and this correlated with decreased microRNA expression and survival. Genome- wide analysis identified numerous microRNAs that were differentially expressed between glioblastomas with low versus high DICER1 expression. Cdk6, which promotes cell cycle progression, was a predicted target of several of these microRNAs. DICER1 knockdown in glioblastoma cells increased cell growth and upregulated Cdk6 protein expression. Importantly, Cdk6 protein was overexpressed in glioblastomas with low DICER1 expression, suggesting that Cdk6 upregulation may be one mechanism by which defective microRNA biogenesis contributes to increased tumor aggressiveness. This innovative and ambitious project will integrate mass spectrometry proteomics, genomics and clinical variables to comprehensively identify the mechanisms underlying the decreased cancer survivorship associated with dysregulated microRNA biogenesis.

最近对人类癌症的研究发现，促进肿瘤发生的microRNA生物发生存在缺陷肿瘤的侵袭性和通过鲜为人知的机制降低存活率。大部分通过microRNAs控制蛋白质的表达而不改变mRNA的表达，并且单个microRNAs可能以组织特异性的方式靶向数十个mRNAs。因此，这个基础广泛的 MicroRNA合成的减少给那些试图了解其下游的人带来了挑战癌症发生的分子效应。在这里，我们提出了一项新的战略，将全面确定microRNA生物发生缺陷降低癌症存活率的机制。该方法涉及基因组规模的高通量定量质量的整合全基因组microRNA、mRNA和DNA对肿瘤蛋白质组的光谱分析分析具有完整或缺陷microRNA生物发生的人脑肿瘤(胶质母细胞瘤)。结合临床变量的新算法将被用来生成完整的基因组- 已识别的差异和临床相关靶点的比例视图将使用体内模型和体外模型。我们实验室应用aCGH和mRNA微阵列的初步研究发现DICER1基因缺失并降低了DICER1基因的表达胶质母细胞瘤，这与microRNA表达减少和存活率相关。基因组- 广泛的分析发现了大量差异表达的microRNA DICER1低表达与高表达的胶质母细胞瘤。促进细胞周期的CDK6 进展，是这些microRNA中的几个预测的目标。DICER1击倒在胶质母细胞瘤细胞促进细胞生长，上调CDK6蛋白表达。重要的是 CDK6蛋白在DICER1低表达的胶质母细胞瘤中高表达，提示 CDK6上调可能是microRNA生物发生缺陷导致肿瘤侵袭性增加。这一创新和雄心勃勃的项目将把群众光谱蛋白质组学、基因组学和临床变量综合鉴定与调节失调的microRNA相关的癌症存活率下降的机制生物发生学。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Alternative splicing of CHEK2 and codeletion with NF2 promote chromosomal instability in meningioma.

CHEK2 的选择性剪接以及与 NF2 的共缺失会促进脑膜瘤中的染色体不稳定。

DOI：
10.1593/neo.111574
发表时间：
2012
期刊：
Neoplasia (New York, N.Y.)
影响因子：
0
作者：
Yang,HongWei;Kim,Tae-Min;Song,SydneyS;Shrinath,Nihal;Park,Richard;Kalamarides,Michel;Park,PeterJ;Black,PeterM;Carroll,RonaS;Johnson,MarkD
通讯作者：
Johnson,MarkD

Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes.

DOI：
10.1101/gr.140301.112
发表时间：
2013-02
期刊：
Genome research
影响因子：
7
作者：
Kim TM;Xi R;Luquette LJ;Park RW;Johnson MD;Park PJ
通讯作者：
Park PJ

A small subunit processome protein promotes cancer by altering translation.

一种小亚基加工蛋白通过改变翻译来促进癌症。

DOI：
10.1038/onc.2014.376
发表时间：
2015
期刊：
Oncogene
影响因子：
8
作者：
Yang,HW;Kim,T-M;Song,SS;Menon,L;Jiang,X;Huang,W;Black,PM;Park,PJ;Carroll,RS;Johnson,MD
通讯作者：
Johnson,MD

Numb regulates glioma stem cell fate and growth by altering epidermal growth factor receptor and Skp1-Cullin-F-box ubiquitin ligase activity.

DOI：
10.1002/stem.1120
发表时间：
2012-07
期刊：
STEM CELLS
影响因子：
5.2
作者：
Jiang, Xiuli;Xing, Hongyan;Kim, Tae-Min;Jung, Yuchae;Huang, Wei;Yang, Hong Wei;Song, Shengye;Park, Peter J.;Carroll, Rona S.;Johnson, Mark D.
通讯作者：
Johnson, Mark D.