Determining the mechanistic and therapeutic roles of microRNAs in bladder cancer

确定 microRNA 在膀胱癌中的机制和治疗作用

• 批准号: 7886234
• 负责人: Gangning Liang
• 金额: $ 26.89万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-09 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886234
• 关键词: 3' Untranslated Regions; Binding; Bladder Neoplasm; Bladder Tissue; CMV promoter; Cancer Patient; Cell Line; Cessation of life; Diagnostic; Engineering; Epigenetic Process; Foundations; Functional RNA; Gene Targeting; Genes; Genetic; Goals; Individual; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Messenger RNA; MicroRNAs; National Cancer Institute; Normal tissue morphology; Nucleotides; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Prognostic Marker; Recurrence; Role; Sampling; Staging; Therapeutic; Therapeutic Effect; Transcript; Transitional Cell Carcinoma; Translational Repression; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Urothelial Cell; Vorinostat; Woman; base; cancer cell; cancer diagnosis; cell growth; clinical application; expression vector; flexibility; men; neoplastic cell; novel; novel therapeutics; prognostic; public health relevance; therapeutic target; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): microRNAs (miRNAs) are ~22 nucleotide non-coding RNAs that usually repress genes by imperfectly binding to the 3'UTR of the target mRNA which causes translational repression and mRNA destabilization. miRNA dysregulation has been observed in many cancers and many miRNAs are not only involved in the initiation and progression of cancer but may have therapeutic potential because they target tumor suppressor genes or oncogenes. Bladder cancer, which usually presents as transitional cell carcinoma (TCC), is the fifth most common cancer in the United States. Preliminary results from miRNA profiling indicate that miRNA misexpression has severe consequences in TCC tumorigenesis and some miRNAs may be tumor suppressors or oncogenes. Our study also shows that some silenced tumor suppressor miRNAs can be reactivated by epigenetic treatment. Furthermore, we have developed a flexible platform using the CMV promoter to restore expression of multiple tumor suppressor miRNAs from a single engineered transcript. This novel expression vector can inhibit tumor cell growth by targeting multiple oncogenes or oncogenic pathways. In this proposal, based on our strong preliminary results, we plan to focus on: 1) identifying specific miRNAs for diagnostic and prognostic purposes for bladder cancer patients; 2) reactivating silenced tumor suppressor miRNAs by epigenetic treatment; 3) characterizing the role of miRNAs during tumorigenesis and re-expressing identified tumor suppressor miRNAs in cancer cells with a multiple miRNA expression vector. Completion of these specific aims will provide an important step towards the clinical application of using miRNAs as diagnostic and/or prognostic markers and as therapeutic targets in bladder cancer patients. PUBLIC HEALTH RELEVANCE: In the United States, bladder cancer is the fourth most common cancer diagnosis in men and the eighth most common in women with 50-80% of cases recurring. In 2009 there are estimated 70,980 new cases and 14,330 deaths due to bladder cancer according to the National Cancer Institute. miRNA dysregulation has been observed in many cancers and many miRNAs have therapeutic potential because they target tumor suppressor genes or oncogenes. Completion of this study will provide an exciting step towards the clinical application of using miRNAs as diagnostic and/or prognostic markers and as therapeutic targets in bladder cancer patients.

描述（由申请人提供）：microRNA（miRNA）是〜22个核苷酸非编码RNA，通常通过与靶mRNA的3'UTR结合而抑制基因，从而导致翻译抑制和mRNA不稳定。 在许多癌症中都观察到miRNA失调，许多miRNA不仅参与癌症的起步和进展，而且可能具有治疗潜力，因为它们靶向肿瘤抑制基因或癌基因。 通常以过渡性细胞癌（TCC）表示的膀胱癌是美国第五大癌症。 miRNA分析的初步结果表明，miRNA misexpression对TCC肿瘤发生有严重的后果，而某些miRNA可能是肿瘤抑制剂或癌基因。 我们的研究还表明，一些沉默的肿瘤抑制miRNA可以通过表观遗传治疗重新激活。 此外，我们使用CMV启动子开发了一个灵活的平台，以恢复单个工程转录本的多个肿瘤抑制miRNA的表达。 这种新型的表达载体可以通过靶向多种肿瘤或致癌途径来抑制肿瘤细胞的生长。 在此提案中，基于我们的强烈初步结果，我们计划关注：1）确定特定的miRNA，以识别膀胱癌患者的诊断和预后目的； 2）通过表观遗传治疗重新激活沉默的肿瘤抑制miRNA； 3）表征miRNA在肿瘤发生过程中的作用和重新表达的，鉴定出具有多个miRNA表达载体的癌细胞中肿瘤抑制miRNA。 这些特定目标的完成将为使用miRNA作为诊断和/或预后标记以及作为膀胱癌患者的治疗靶标提供重要的一步。 公共卫生相关性：在美国，膀胱癌是男性中第四个最常见的癌症诊断，也是50-80％病例反复出现的女性中最常见的第八名。 根据国家癌症研究所的数据，2009年估计有70,980例新病例和14,330例死亡。 在许多癌症中观察到miRNA失调，并且许多miRNA具有治疗潜力，因为它们靶向肿瘤抑制基因或癌基因。 这项研究的完成将为使用miRNA作为诊断和/或预后标记以及作为膀胱癌患者的治疗靶标提供令人兴奋的一步。