MicroRNAs in African American Prostate Cancer

非裔美国人前列腺癌中的 MicroRNA

基本信息

批准号：
9374424
负责人：
DEEPAK KUMAR
金额：
$ 36.53万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
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：
2015-07-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9374424
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Affect African American Age Aggressive behavior Anoikis Apoptosis Benign Binding Biological Biological Markers Biopsy Body Fluids Cancer Cell Growth Cancer Patient Caucasians Cell Survival Cells Cessation of life Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Data Death Rate Development Diagnosis Disease Disease Progression Disease Resistance Drug resistance Early Diagnosis Gene Deletion Gene Targeting Health Immunohistochemistry In Situ Hybridization In Vitro Incidence Indolent JUN gene Lasers Link Longitudinal Studies MAPK8 gene Malignant Neoplasms Malignant neoplasm of prostate MicroRNAs Molecular Target N-terminal Neoplasm Metastasis PC3 cell line Pathogenesis Pathology Phenotype Prevention Prostate Proteins Public Health Race Regulator Genes Reporting Resistance Reverse Transcriptase Polymerase Chain Reaction Risk Role Serum Signal Transduction Specificity Staging Structure of base of prostate Therapeutic Time Tissues United States Untranslated RNA Untranslated Regions Urine advanced disease angiogenesis cancer cell cancer genome cancer health disparity cancer initiation cell motility clinically significant differential expression epithelial to mesenchymal transition ethnic diversity genome editing in vivo insight knock-down loss of function men migration molecular marker mouse model new therapeutic target novel nuclease outcome forecast potential biomarker pre-clinical preclinical study prostate cancer cell prostate cancer cell line prostate carcinogenesis therapeutic target therapy development transcription factor tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most common cancer in men in the United States, which disproportionately affects African Americans (AA) with higher incidence, advanced disease and worse prognosis. MicroRNAs (miRNAs) are non-coding RNAs that represent universal gene regulatory mechanism exerting its effect primarily by binding to 3'UTR of target and affect cell survival, proliferation, cancer initiation, development and metastasis. We recently reported differential expression of miRNAs in PCa tissues and body fluids. In this proposal, we present preliminary data on selected two miRNAs that are downregulated in age/disease matched African American (AA) when compared with Caucasian (CA) PCa tissues. We present preliminary data on modulation cancer cell growth, migration, anoikis, angiogenesis and modulation of EMT signaling. We have preliminarily identified several miRNA targets that may explain miRNA mechanisms in PCa progression. We report miRNA modulation of JNK1-Sp1 signaling which is known to modulate angiogenesis and metastasis. We hypothesize that differential loss of selected microRNAs in AA PCa deregulates an intricate signaling network, leading to aggressive phenotype. Further these miRNAs could be used as biomarkers to distinguish between indolent vs. aggressive disease (predominant in AAs) and serve as novel therapeutic targets. The specific aims of this proposal are: (1) to study the clinical significance of microRNAs and their targets in age/race matched PCa tissues and their adjacent benign regions and disease staged PCa TMAs; (2) to validate miRNA targets and delineate signaling mechanisms by generating miRNA gene deletions in AA and CA prostate cells by genome editing using [Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR associated (CAS) nuclease Cas9); (3) Investigate the role of microRNAs in experimental prostate carcinogenesis in vitro and in vivo by studying their gain and loss of function in AA and CA prostate cancer cells and in vivo by examining the effects on tumor growth and metastasis in an orthotopic mouse model. Recognizing miRNAs as basis of PCa pathogenesis, disparity and understanding their biological implications will significantly impact diagnosis and treatment development for aggressive PCa common in African American men.

描述（由适用提供）：前列腺癌（PCA）是美国男性中最常见的癌症，它对非洲裔美国人（AA）不成比例，患有较高的事件，晚期疾病和较差的预后。 MicroRNA（miRNA）是非编码RNA，代表通用基因调节机制，通过与靶标的3'UTR结合并影响细胞存活，增殖，癌症起始，发育和转移来发挥其作用。我们最近报道了PCA组织和体液中miRNA的差异表达。在此提案中，我们介绍了与高加索（CA）PCA组织相比，在年龄/疾病匹配的非裔美国人（AA）中被下调的两个miRNA的初步数据。我们介绍了有关调节癌细胞生长，迁移，Anoikis，血管生成和EMT信号传导调节的初步数据。我们初步确定了几个可能解释PCA进展中的miRNA机制的miRNA靶标。我们报告了JNK1-SP1信号传导的miRNA调节，该信号传导可调节血管生成和转移。我们假设AA PCA中选定的microRNA的差异丢失会导致复杂的信号网络，从而导致侵略性表型。此外，这些miRNA可以用作生物标志物，以区分indolort and侵袭性疾病（AAS中的占主导地位）并用作新的治疗靶标。该提案的具体目的是：（1）研究microRNA及其在年龄/种族中的临床意义与PCA组织相匹配的PCA组织及其邻近的良性区域以及疾病上演的PCA TMA；（2）通过使用[簇状的定期插入的短期短质体重复序列（CRISPR）/CRISPR相关（CAS）Nuclease（CAS）nuclease cas9）通过基因组编辑在AA和CA前列腺细胞中产生miRNA基因缺失来验证miRNA靶标和描述信号传导机制；（3）通过研究其在AA和CA前列腺癌细胞中其功能的增益和功能丧失以及体内的作用，研究了microRNAS在实验性前列腺癌中的作用，并通过检查对正位小鼠模型中对肿瘤生长和转移的影响，并在体内进行体内。将miRNA视为PCA发病机理的基础，差异和理解其生物学意义将显着影响非裔美国人男性常见的侵略性PCA的诊断和治疗开发。