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（由申请人提供）：尽管作为癌症遗传学和最近的基因组学的最初试验场，结直肠癌（CRC）仍然是一种致命的疾病。缺乏重大突破的一个原因是，专注于单个信号通路不足以理解这种疾病的发病机制和进展。MYC癌基因就是一个很好的例子。它涉及到令人眼花缭乱的功能相互作用，其中很少有被完全理解或充分验证的。该补助金的首要目标是确定可用于治疗的MYC途径相互作用。在CRC中，由于WNT途径中的激活突变，MYC经常过表达。WNT配体与共受体FZD和LRP的结合防止APC肿瘤抑制剂介导的β-连环蛋白降解。稳定的β-连环蛋白易位到细胞核中，在那里它与TCF 4转录因子形成复合物并驱动MYC表达。然而，哪些非突变事件有助于WNT依赖性Myc激活在很大程度上仍然未知。MYC在高度遗传复杂的CRC中的功能也没有被牢固地确立。我们最近证明MYC赋予CRC细胞多血管表型。这是通过下调血小板反应蛋白-1（Tsp 1）和相关的抗血管生成因子发生的，其中许多因子通常由转化生长因子β维持。TGF β通路在CRC中也经常失活，但它如何通过非突变手段进行调节仍有待观察。在过去的几年中，我们发现Myc远不是WNT和TGF β信号传导的被动下游效应子，而是具有深刻影响这两种途径的潜力。这在很大程度上是由于Myc上调miR-17~92 microRNA簇的能力（又称Myc基因）。oncomir-1）。与该提议相关的是，在CRC中，miR-17-92直接靶向并下调Tsp 1，但具有更广泛的影响-TGF β途径的几个关键组分。其他相关Myc| miR-17~92的靶点是DKK 3，DKK 3是一种抑制性LRP配体和WNT信号抑制剂。这些发现导致了以下总体假设：WNT、Myc和miR-17~92形成了以前未被认识到的正反馈环，其抑制TGF β信号传导并促进肿瘤新生血管形成。在本建议中，我们的目标是：1。定义DKK 3在维持Myc表达中的作用; 2.确定Wnt的作用|Myc| miR-17~92克服TGF β对血管生成的抑制作用; 3. TGF β 1通路突变作为靶向WNT通路药物耐药性的决定因素。在实现本提案的三个目标后，我们将重新绘制人类CRC的接线图，确定治疗性抗血管生成的新靶点，并利用癌症基因组学的力量来预测对靶向WNT和TGF β通路的新药的反应。