The Akt-associated microRNAs in cancer cells

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。作为主控基因调控因子，microrna影响多种细胞通路。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，并且它们可能作为癌基因或肿瘤抑制因子起作用。令人感兴趣的是，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，抑制Akt诱导miR-145表达；另一方面，miR-101激活Akt，促进雌激素独立生长和他莫昔芬耐药。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它们的细胞功能。因此，更好地了解这种Akt- microrna调控网络对于成功靶向PI3K/Akt通路进行癌症治疗至关重要。我们在此应用程序中提出三个具体目标。第一个目标将侧重于miR-145。我们将确定miR-145调控的潜在机制，并将确定miR-145如何通过PI3K/Akt通路在肿瘤中下调。目的2是剖析microrna介导的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，并解剖miR-101介导的Akt活化的分子和细胞事件。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）之间是否存在相关性；我们还将确定miR-101在对他莫昔芬具有内在抗性的ER阳性乳腺肿瘤中是否失调。总之，这项工作将更好地了解akt相关的microrna和基因调控的潜在机制，导致肿瘤的发生、发展和抗激素抵抗。

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.