The Akt-associated microRNAs in cancer cells

癌细胞中与 Akt 相关的 microRNA

• 批准号: 8185398
• 负责人: YIN-YUAN MO
• 金额: $ 28.3万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-06 至 2012-03-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185398
• 关键词: Biological Markers; CCAAT-Enhancer-Binding Proteins; Cancer Patient; Cell Proliferation; Cell physiology; Code; Diagnosis; Disease; Endocrine; Estrogens; Event; Gene Expression Regulation; Genes; Goals; Growth; Human; Lead; Libraries; Link; Malignant Neoplasms; Mammary Neoplasms; Mediating; MicroRNAs; Molecular; Molecular Target; Neoplasm Metastasis; Oncogenes; Pathway interactions; Phosphatidylinositols; Phosphotransferases; Play; Process; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Regulator Genes; Reporter; Reporting; Resistance; Role; Signal Pathway; Specimen; Staging; System; Tamoxifen; Translational Repression; Tumor Cell Invasion; Tumor Suppressor Proteins; Update; Work; cancer cell; cancer diagnosis; cancer initiation; cancer prevention; cancer therapy; cancer type; cell growth; clinically significant; hormone resistance; improved; interest; mRNA Transcript Degradation; member; mutant; new therapeutic target; novel; therapeutic target; tumor; tumor growth; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): The goal of this application is to investigate the role of Akt-associated microRNAs in cancer. As master gene regulators, microRNAs impact diverse cellular pathways. Accumulating evidence indicates that microRNAs are often dysregulated in many types of human cancers, and that they may function as oncogenes or tumor suppressors. Of considerable interest, our preliminary studies suggest that microRNA pathways interconnect with the Akt pathway, forming Akt-microRNA regulatory network. For example, suppression of Akt induces miR-145 expression; on the other hand, miR-101 causes activation of Akt, and it promotes estrogen independent growth and tamoxifen resistance. Thus, they belong to a class of Akt-associated microRNAs. We hypothesize that microRNAs and Akt in this network work together to exert their cellular functions. Therefore, a better understanding of this Akt-microRNA regulatory network is critical to successful targeting of the PI3K/Akt pathway for cancer therapy. We propose three specific aims in this application. The first aim will focus on miR-145. We will determine the underlying mechanism of miR-145 regulation, and will determine how miR-145 is downregulated in tumors through the PI3K/Akt pathway. Aim 2 is to dissect the molecular pathway of microRNA-mediated Akt activation. Specifically, we will determine how miR-101 induces Akt activity and dissect molecular and cellular events of miR-101- mediated Akt activation. The third aim is to determine the clinical significance of miR-145 and miR- 101. We will determine whether there is any correlation between miR-145 and clinicopathologic features such as disease stage, metastasis status or other features; we will also determine whether miR-101 is dysregulated in ER positive breast tumors that are intrinsically resistant to tamoxifen. Together, the proposed work will provide a better understanding of Akt-associated microRNAs and the underlying mechanism of gene regulation, leading to tumor initiation, progression and anti-hormone resistance. PUBLIC HEALTH RELEVANCE: MicroRNAs are master gene regulators that are capable of targeting protein-coding genes by translational repression or mRNA degradation. Overwhelming evidence indicates that microRNAs play a causal role in human malignancies. Therefore, a better understanding of how microRNAs regulate cellular pathways, ultimately causing cancer initiation, progression and endocrine resistance will aid in the identification of cancer biomarkers and/or novel therapeutic targets and provide direct benefit to cancer patients.

描述（由申请人提供）：本申请的目的是研究与Akt相关的microRNA在癌症中的作用。作为主基因调节剂，microRNA会影响各种细胞途径。积累的证据表明，在许多类型的人类癌症中，microRNA通常会失调，并且它们可能充当癌基因或肿瘤抑制子。我们的初步研究引起了人们的关注，这表明MicroRNA途径与AKT途径相互连接，形成了Akt-Microrna调节网络。例如，抑制AKT会诱导miR-145表达。另一方面，miR-101引起AKT的激活，并促进雌激素独立的生长和他莫昔芬的耐药性。因此，它们属于一类与Akt相关的microRNA。我们假设该网络中的microRNA和AKT共同发挥其细胞功能。因此，更好地理解该AKT-Microrna调节网络对于成功靶向PI3K/AKT癌症治疗途径至关重要。我们在此应用中提出了三个具体目标。第一个目标将集中于mir-145。我们将确定miR-145调控的潜在机制，并将确定通过PI3K/AKT途径在肿瘤中miR-145的下调。 AIM 2是剖析microRNA介导的Akt激活的分子途径。具体而言，我们将确定miR-101如何诱导MiR-101-介导的Akt激活的Akt活性并剖析分子和细胞事件。第三个目的是确定miR-145和miR-101的临床意义。我们将确定miR-145与临床病理学特征（例如疾病阶段，转移状态或其他特征）之间是否存在任何相关性；我们还将确定miR-101是否在对他莫昔芬具有本质上抗性的阳性乳腺肿瘤中失调。总之，拟议的工作将更好地理解与Akt相关的microRNA和基因调节的潜在机制，从而导致肿瘤起步，进展和抗激素耐药性。 公共卫生相关性：microRNA是主要基因调节剂，能够通过翻译抑制或mRNA降解来靶向蛋白质编码基因。压倒性的证据表明，microRNA在人类恶性肿瘤中起因作用。因此，更好地了解microRNA如何调节细胞途径，最终导致癌症的启动，进展和内分泌耐药性将有助于鉴定癌症生物标志物和/或新型的治疗靶标，并为癌症患者提供直接益处。