The Role of MicroRNAs in Prostate Cancer Progression

MicroRNA 在前列腺癌进展中的作用

• 批准号: 7662900
• 负责人: Aurora Esquela Kerscher
• 金额: $ 7.18万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662900
• 关键词: Affect; Animals; Apoptosis; Area; Attention; Benign Prostatic Hypertrophy; Binding; Bioinformatics; Biological Assay; Biological Markers; Cancer Control; Cancerous; Cell Death; Cell Growth Processes; Cell Line; Cessation of life; Code; Control Animal; Country; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Event; Family; Functional RNA; Gene Expression; Gene Targeting; Genes; Goals; Growth; Human; In Situ; Incidence; Lead; Length; Life; Life Expectancy; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Messenger RNA; MicroRNAs; Microarray Analysis; Molecular Profiling; Nucleotides; Oncogenic; Patients; Pattern; Plants; Process; Prostate; Prostate carcinoma; Prostate-Specific Antigen; Proteins; Public Health; Reporter Genes; Role; Screening for Prostate Cancer; Specimen; Staging; Techniques; Testing; Time; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Tumor Suppressor Genes; United States; Virginia; Work; cell growth; cell transformation; cohort; improved; innovation; male; member; men; metaplastic cell transformation; metropolitan; mortality; novel; novel strategies; prevent; tumor; tumor progression

DESCRIPTION (provided by applicant): Prostate cancer is the most common form of cancer in males within the United States. This prevalent disease was responsible for ~27,000 deaths last year, a mortality rate in men second only to lung cancer. Prostate-specific antigen (PSA) is a widely used diagnostic marker for prostate cancer that can result in the treatment of insignificant disease due in part because PSA is tissue specific but not prostate cancer specific. Therefore, more accurate biomarkers, potentially used in combination with PSA, are required to aid in the early diagnosis of prostate cancer. An abundant class of small non-coding RNAs of ~22 nucleotides in length, referred to as microRNAs (miRNAs), are often misexpressed in human cancers and implicated to function as tumor suppressors and oncogenes. However, little is known regarding how these molecules directly contribute to cellular transformation and cancer progression or how miRNA deregulation relates to prostate cancer. SPECIFIC AIMS: The hypothesis to be tested is that miRNAs controlling proper cellular growth and differentiation in the prostate will be deregulated in the diseased state and thus miRNA misexpression will closely correlate with early stages of prostate cancer progression and micrometastatic disease. We particularly anticipate identifying members of the evolutionary conserved lin-4 and let-7 miRNA families, which we have shown control essential developmental events in animals and are linked with human cancers. This proposal will 1) identify miRNAs that are deregulated in a large cohort (~250) of tissue samples taken from patients with prostate carcinomas including insignificant and micrometastatic disease compared to non-cancerous specimens from benign prostatic hyperplasia (BPH) patients and normal prostate tissues via miRNA microarray analysis and quantitative real-time PCR; 2) determine the gene targets of prostate cancer-associated miRNAs that direct oncogenic events using bioinformatic screens and reporter gene assays; and 3) investigate if these prostate cancer-associated miRNA-target interactions are directly involved in cancer progression by in situ expression analysis on normal and diseased prostate tissue specimens and miRNA misexpression studies in human prostate cell lines to analyze resulting affects on growth modulation and cellular transformation. The overall goal of this proposal is to identify miRNA genes that could serve as early detection biomarkers for prostate cancer and to determine how these miRNAs and their potential targets control tumor formation in this tissue. Investigating the function of miRNAs in prostate cancer progression promises to reveal novel strategies to detect & treat this prevalent disease.

描述（由申请人提供）： 前列腺癌是美国男性最常见的癌症形式。这种流行的疾病去年造成约27，000人死亡，男性死亡率仅次于肺癌。前列腺特异性抗原（PSA）是一种广泛使用的前列腺癌诊断标志物，部分原因是PSA具有组织特异性，但不是前列腺癌特异性，因此可以治疗不显著的疾病。因此，需要更准确的生物标志物，可能与PSA联合使用，以帮助前列腺癌的早期诊断。一类丰富的长度约为22个核苷酸的小非编码RNA，称为microRNA（miRNA），通常在人类癌症中错误表达，并涉及作为肿瘤抑制因子和癌基因发挥功能。然而，关于这些分子如何直接促进细胞转化和癌症进展或miRNA失调如何与前列腺癌相关的知之甚少。具体目标：待检验的假设是，控制前列腺中适当细胞生长和分化的miRNA将在患病状态下被解除调节，因此miRNA错误表达将与前列腺癌进展和微转移疾病的早期密切相关。我们特别期待鉴定进化上保守的lin-4和let-7 miRNA家族的成员，我们已经证明这些家族控制着动物的基本发育事件，并与人类癌症有关。该建议将1）通过miRNA微阵列分析和定量实时PCR鉴定与来自良性前列腺增生（BPH）患者和正常前列腺组织的非癌样本相比，在取自前列腺癌患者的大组（~250）组织样本（包括不显著和微转移性疾病）中失调的miRNA; 2）使用生物信息学筛选和报告基因测定来确定指导致癌事件的前列腺癌相关miRNA的基因靶标;以及3）研究这些前列腺癌相关的miRNA-通过对正常和患病前列腺组织标本的原位表达分析和人前列腺细胞系中的miRNA错误表达研究来分析对生长调节的影响，细胞转化该提案的总体目标是鉴定可作为前列腺癌早期检测生物标志物的miRNA基因，并确定这些miRNA及其潜在靶点如何控制该组织中的肿瘤形成。研究miRNAs在前列腺癌进展中的功能有望揭示检测和治疗这种流行疾病的新策略。