The Myc - miR-17-92 axis in colorectal cancers

结直肠癌中的 Myc - miR-17-92 轴

• 批准号: 9251789
• 负责人: Andrei Thomas-Tikhonenko
• 金额: $ 38.43万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251789
• 关键词: Alleles; Alpha Cell; Angiogenic Factor; Antineoplastic Agents; ApcMin/+ mice; Attenuated; Binding; Blood Vessels; Cell Nucleus; Cells; Clinical Trials; Colon; Colorectal Cancer; Complement Factor B; Complex; Disease; Disease Progression; Down-Regulation; Drug Targeting; Drug resistance; Elements; Event; Feedback; Genes; Genetic Transcription; Genomics; Goals; Grant; Human; Hypervascular; Individual; Innovative Therapy; KRAS2 gene; Ligands; MYC gene; Measures; Mediating; MicroRNAs; Modeling; Mus; Mutation; Neoplasms in Vascular Tissue; Paper; Pathogenesis; Pathway interactions; Phenotype; Publishing; Resistance; Role; Signal Pathway; Signal Transduction; T cell factor 4; TGFBR1 gene; Testing; The Cancer Genome Atlas; Thrombospondin 1; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Suppressor Proteins; WNT Signaling Pathway; angiogenesis; antiangiogenesis therapy; beta catenin; cancer genetics; cancer genomics; colon cancer cell line; exhaustion; genome-wide; in vivo; inhibitor/antagonist; mimetics; neovascularization; new therapeutic target; overexpression; patient subsets; predicting response; pressure; prevent; public health relevance; receptor; response; restoration; small molecule; targeted treatment; tumor

 DESCRIPTION (provided by applicant): Despite serving as the initial testing ground for cancer genetics and more recently - genomics, colorectal cancer (CRC) remains a deadly disease. One reason for the lack of major breakthroughs is that focusing on individual signaling pathways is not enough to understand pathogenesis and progression of this disease. The MYC oncogene is a case in point. It is involved in a dizzying number of functional interactions, few of which have been fully understood or sufficiently validated. The overarching goal of this grant is to identify MYC pathway interactions that can be targeted therapeutically. In CRC, MYC is frequently overexpressed due to activating mutations in the WNT pathway. Binding of WNT ligands to the co-receptors FZD and LRP prevents APC tumor suppressor-mediated degradation of ß-catenin. Stabilized ß-catenin translocates into the nucleus, where it forms a complex with the TCF4 transcription factor and drives MYC expression. However, what non-mutational events aid WNT-dependent Myc activation remains largely unknown. Nor has MYC function in highly genetically complex CRC been firmly established. We recently demonstrated that MYC confers upon CRC cells a hypervascular phenotype. This occurs through down-regulation of thrombospondin-1 (Tsp1) and related anti-angiogenic factors, many of which are normally sustained by transforming growth factor ß. The TGFß pathway, too, is frequently inactivated in CRC, but how it is regulated by non-mutational means remained to be seen. In the past several years we discovered that far from being a passive downstream effector of WNT and TGFß signaling, Myc has the potential to profoundly influence both pathways. This is due in large part to the ability o Myc to up-regulate the miR-17~92 microRNA cluster (a.k.a. oncomir-1). Of relevance to this proposal, in CRC miR-17-92 directly targets and down-regulates Tsp1, but with even broader impact - several key components of the TGFß pathway. Another relevant Myc | miR-17~92 target is DKK3, an inhibitory LRP ligand and WNT signaling suppressor. These discoveries have led to the following overall hypothesis: WNT, Myc, and miR-17~92 form a previously unrecognized positive feedback loop, which suppresses TGFß signaling and promotes tumor neovascularization. In this proposal, we aim to: 1. Define a role of DKK3 in sustaining Myc expression; 2. Determine the role of Wnt | Myc | miR-17~92 in overcoming angiogenesis suppression by TGFß; 3. Validate TGFß pathway mutations as determinants of resistance to drugs targeting the WNT pathway. After fulfilling the three Aims of this proposal we will have re-drawn the wiring diagrams of human CRC, identified novel targets for therapeutic anti-angiogenesis, and harnessed the power of cancer genomics to predict responses to new drugs targeting WNT and TGFß pathways.

 描述（由适用提供）：尽管是癌症遗传学的初始测试基础，而最近 - 基因组学，有色癌症（CRC）仍然是一种致命的疾病。缺乏重大突破的原因之一是，专注于单个信号通路不足以了解该疾病的发病机理和进展。 Myc癌基因是一个很好的例子。它参与了许多功能相互作用，其中很少有完全理解或充分验证的功能相互作用。这笔赠款的总体目标是确定可以针对理论的MYC途径相互作用。在CRC中，由于WNT途径中激活突变，MYC经常过表达。 Wnt配体与共受体FZD和LRP的结合可防止APC抑制剂介导的β-catenin的降解。稳定的ß-catenin易位到细胞核中，在那里它与TCF4转录因子形成复合物并驱动MYC的表达。但是，哪些非灭菌事件有助于Wnt依赖MYC激活，在很大程度上未知。 MYC在高度一般复杂的CRC中也没有首次建立。我们最近证明了MYC细胞在CRC细胞上包含一个血管过血管表型。这是通过下调血小板蛋白-1（TSP1）和相关的抗血管生成因子而发生的，其中许多因素通常是通过转化生长因子ß来维持的。 TGFß路径也经常在CRC中灭活，但是如何通过非灭菌手段来调节它。在过去的几年中，我们发现MYC并不是Wnt和TGFß信号传导的被动下游效应器，而是有可能深刻影响这两种途径。这在很大程度上归功于Myc上调miR-17〜92 microRNA簇（又称oncomir-1）的能力。与该提案相关的是，在CRC miR-17-92中，直接靶向并下调TSP1，但影响更大 - TGFß途径的几个关键组成部分。另一个相关的MYC | miR-17〜92靶标是DKK3，是抑制性LRP配体和Wnt信号抑制器。这些发现导致了以下总体假设：Wnt，MYC和miR-17〜92形成了先前未识别的阳性反馈回路，从而抑制TGFß信号传导并促进肿瘤新生血管形成。在此提案中，我们的目标是：1。定义DKK3在维持MYC表达中的作用； 2。确定Wnt的作用| MYC | MiR-17〜92在克服TGFß抑制血管生成的过程中； 3。验证TGFß途径突变是针对靶向Wnt途径的药物的抗性的决定剂。在实现了该提案的三个目标之后，我们将重新划出人类CRC的接线图，确定了治疗性抗血管生成的新目标，并利用了癌症基因组学的能力来预测针对WNT和TGFß途径的新药物的反应。