The Akt-associated microRNAs in cancer cells

癌细胞中与 Akt 相关的 microRNA

• 批准号: 8530179
• 负责人: YIN-YUAN MO
• 金额: $ 29.16万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530179
• 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.

描述（由申请人提供）：本申请的目的是研究Akt相关microRNA在癌症中的作用。作为主基因调节因子，microRNA影响多种细胞途径。越来越多的证据表明，microRNA在许多类型的人类癌症中经常失调，并且它们可能作为致癌基因或肿瘤抑制因子发挥作用。值得注意的是，我们的初步研究表明microRNA通路与Akt通路相互连接，形成Akt-microRNA调控网络。例如，Akt的抑制诱导miR-145表达;另一方面，miR-101引起Akt的激活，并且其促进雌激素非依赖性生长和他莫昔芬抗性。因此，它们属于一类Akt相关的microRNA。我们假设，microRNA和Akt在这个网络中共同发挥其细胞功能。因此，更好地理解这种Akt-microRNA调控网络对于成功靶向PI 3 K/Akt通路用于癌症治疗至关重要。我们在本申请中提出三个具体目标。第一个目标将集中在miR-145上。我们将确定miR-145调控的潜在机制，并确定miR-145如何通过PI 3 K/Akt途径在肿瘤中下调。目的二是探讨microRNA介导Akt活化的分子途径。具体而言，我们将确定miR-101如何诱导Akt活性，并分析miR-101介导的Akt激活的分子和细胞事件。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与临床病理特征（如疾病分期、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内在耐药性的ER阳性乳腺肿瘤中失调。总之，拟议的工作将提供对Akt相关microRNA和基因调控的潜在机制的更好理解，从而导致肿瘤的发生，进展和抗激素抵抗。