Molecular biomarkers for kidney cancer prognosis using non-coding RNAs

使用非编码 RNA 进行肾癌预后的分子生物标志物

• 批准号: 9270533
• 负责人: RAJVIR DAHIYA
• 金额: $ 35.07万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270533
• 关键词: Address; Apoptosis; Binding; Biological Assay; Biological Markers; Cancer Patient; Cancer Prognosis; Cancer cell line; Cell Line; Cell Proliferation; Clinical; Clinical assessments; Complex; Data; EZH2 gene; Epithelial; Flow Cytometry; Genes; Genetic Markers; Goals; Growth; HK2 gene; Histologic; Implant; In Situ Hybridization; In Vitro; Indolent; Kidney; Lipofectamine; Liver; Lung; MALAT1 gene; Malignant - descriptor; Mesenchymal; Methods; MicroRNAs; Molecular; Molecular Mechanisms of Action; Mus; Neoplasm Metastasis; Nuclear; Nude Mice; Oncogenic; Organ; Outcome; Pathologic; Pathway interactions; Polycomb; Prognostic Marker; RNA analysis; Reagent; Renal carcinoma; Risk Assessment; Role; Small Interfering RNA; Snails; Techniques; Technology; Testing; Time; Transfection; Untranslated RNA; Vimentin; base; bone; cancer cell; capsule; clinical predictors; differential expression; experimental study; histone modification; in vitro Model; in vivo; in vivo Model; innovation; kidney epithelial cell; lymph nodes; migration; molecular marker; overexpression; predict clinical outcome; prognostic; public health relevance; screening; slug; therapeutic target; tumor progression

 DESCRIPTION (provided by applicant): The main goal of this project is to develop prognostic biomarkers based on long non-coding RNA analysis that can predict risk assessment of kidney cancer. The major problem or critical barrier in the field is that there are no biomarkers or methods to predict clinical outcome of kidney cancer. To address this problem, we will investigate whether long non-coding RNAs (lncRNAs) can be used as genetic biomarkers to predict which localized indolent kidney cancers are likely to progression and metastasize. Original Hypotheses: The proposed hypotheses are radically different and innovative. The first hypothesis is that the differential expression of oncogenic lncRNAs HOTAIR and MALAT1 and their binding miRNAs in different stages and grades of kidney cancer may serve as prognostic biomarkers. The second hypothesis is that suppression of oncogenic MALAT1 and HOTAIR by siRNAs or activation of their binding miRNAs will inhibit kidney cancer growth and progression using both in vitro and in vivo models. The third hypothesis is that the molecular mechanisms of oncogenic long non-coding RNAs HOTAIR and MALAT1 action is through binding to polycomb repressive complex 2, [PRC2 (EZH2 / SUZ12 / EED)] that in turn modulates histone modification complexes, activates epithelial-mesenchymal transition pathway genes (snail, slug, twist, vimentin, ZEB1 and ZEB2) and induces kidney cancer progression. To address these hypotheses, we have proposed the following specific aims. Specific Aim # 1. Investigate whether MALAT1, HOTAIR and their regulatory miRNAs are genetic biomarkers to help in the clinical assessment of kidney cancer. Specific Aim # 2. Investigate the functional significance of non-coding RNAs in suppression of kidney cancer growth and progression using both in vitro and in vivo models. Specific Aim # 3. Investigate the molecular mechanisms of action of MALAT1 and HOTAIR in kidney cancer growth and progression. Impact: This project has high impact because it will investigate the role of non-coding RNAs as genetic biomarkers for risk assessment of kidney cancer. We will investigate the functional significance of non-coding RNAs in kidney cancer using both in vitro and in vivo models. We will also investigate the molecular mechanisms of action of non-coding RNAs through binding to PCR2 that in turn modulates histone modification complexes, activates EMT genes and induces kidney cancer progression. The proposed concepts, methods and technology will advance the field of non-coding RNAs as genetic biomarkers and potential therapeutic targets for the management of kidney cancer.

 描述（由申请人提供）：该项目的主要目标是开发基于长非编码RNA分析的预后生物标志物，其可以预测肾癌的风险评估。该领域的主要问题或关键障碍是没有生物标志物或方法来预测肾癌的临床结果。为了解决这个问题，我们将研究长链非编码RNA（lncRNA）是否可以用作遗传生物标志物来预测哪些局部惰性肾癌可能进展和转移。原始假设：提出的假设是完全不同的和创新的。第一个假设是，致癌lncRNAs HOTAIR和MALAT 1及其结合miRNA在不同阶段和级别的肾癌中的差异表达可作为预后生物标志物。第二个假设是，使用体外和体内模型，通过SiRNA抑制致癌MALAT 1和HOTAIR或激活其结合miRNA将抑制肾癌的生长和进展。第三个假设是致癌长非编码RNA HOTAIR和MALAT 1作用的分子机制是通过与多梳抑制复合物2 [PRC 2（EZH 2/SUZ 12/ EED）]结合，PRC 2进而调节组蛋白修饰复合物，激活上皮-间充质转化途径基因（snail，slug，twist，vimentin，ZEB 1和ZEB 2）并诱导肾癌进展。为了解决这些假设，我们提出了以下具体目标。具体目标#1。研究MALAT 1、HOTAIR及其调节性miRNA是否是有助于肾癌临床评估的遗传生物标志物。具体目标#2。使用体外和体内模型研究非编码RNA在抑制肾癌生长和进展中的功能意义。具体目标#3。研究MALAT 1和HOTAIR在肾癌生长和进展中的分子作用机制。影响：该项目具有很高的影响力，因为它将研究非编码RNA作为肾癌风险评估的遗传生物标志物的作用。我们将使用体外和体内模型研究非编码RNA在肾癌中的功能意义。我们还将研究非编码RNA通过与PCR 2结合的分子作用机制，PCR 2反过来调节组蛋白修饰复合物，激活EMT基因并诱导肾癌进展。所提出的概念、方法和技术将推进非编码RNA作为遗传生物标志物和潜在治疗靶点用于肾癌管理的领域。