The Role of MicroRNAs in Prostate Cancer Progression

MicroRNA 在前列腺癌进展中的作用

• 批准号: 7864214
• 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/7864214
• 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导致约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记物，可能导致治疗无关紧要的疾病，部分原因是PSA是组织特异性的，但不是特定于前列腺癌。因此，需要更准确的生物标志物与PSA结合使用，以帮助早期诊断前列腺癌。长度约为22个核苷酸的大量小型非编码RNA，称为microRNA（miRNA），通常在人类癌症中被染色，并被牵涉到肿瘤抑制剂和癌基因的作用。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放松管制与前列腺癌的关系知之甚少。具体目的：要检验的假设是，控制适当的细胞生长和前列腺分化的miRNA将在患病状态下受管制，因此miRNA misexpression将与前列腺癌进展和微量含量疾病的早期阶段密切相关。我们特别预料到鉴定进化保守的LIN-4和Let-7 miRNA家族的成员，我们已经显示了动物中基本的发展事件，并与人类癌症有联系。该提议将1）确定在从前列腺癌患者（包括微不足道和微量转移性疾病）中取出的大量队列（〜250）中放松管制的miRNA，与来自良性前列腺增生（BPH）患者的非癌性标本相比，与非癌性标本相比，通过mirna Micraaray Micraray分析和定量真实的PRCR; 2）确定使用生物信息学筛选和报告基因测定的前列腺癌相关的miRNA的基因靶标，这些miRNA与癌症相关的miRNA。 3）研究这些前列腺癌相关的miRNA-target相互作用是否通过对正常和患病的前列腺组织标本和人类前列腺细胞系中的miRNA misexpression进行原位表达分析直接参与癌症的进展，从而分析了对生长模拟和细胞转化的影响。该提案的总体目标是鉴定可以用作前列腺癌的早期检测生物标志物的miRNA基因，并确定这些miRNA及其潜在靶标如何控制该组织中的肿瘤形成。研究miRNA在前列腺癌进展中的功能有望揭示发现和治疗这种普遍疾病的新型策略。