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

基本信息

批准号：
9052372
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
项目类别：
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/9052372
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 Health 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 Pathway interactions Polycomb Prognostic Marker RNA analysis Reagent Renal carcinoma Risk Assessment Role Snails Staging Techniques Technology Testing Time Transfection Untranslated RNA Vimentin base bone cancer cell capsule differential expression histone modification in vitro Model in vivo in vivo Model innovation kidney epithelial cell lymph nodes migration molecular marker overexpression predict clinical outcome prognostic research study screening slug therapeutic target tumor progression

项目摘要

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，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。为了解决这个问题，我们将研究长非编码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进展。最初的假设：所提出的假设是完全不同且具有创新性的。第一个假设是，致癌性 lncRNA HOTAIR 和 MALAT1 及其结合 miRNA 在肾癌的不同阶段和级别中的差异表达可能作为预后生物标志物。使用体外和体内模型，通过 siRNA 抑制致癌的 MALAT1 和 HOTAIR 或激活它们的结合 miRNA 将抑制肾癌的生长和进展。致癌长链非编码 RNA HOTAIR 和 MALAT1 作用的分子机制是通过与多梳抑制复合物 2 (PRC2 (EZH2 / SUZ12 / EED)) 结合，进而调节组蛋白修饰复合物，激活上皮间质转化途径基因 (snail 、slug、twist、vimentin、ZEB1 和 ZEB2）并诱导肾癌进展。为了解决这些假设，我们有。具体目标#1.研究MALAT1、HOTAIR及其调节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.研究非编码RNA在抑制肾癌中的功能意义。使用体外和体内模型研究肾癌的生长和进展具体目标 # 3. 研究 MALAT1 和 HOTAIR 在肾癌生长和进展中的分子作用机制影响：该项目具有以下作用。影响很大，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。非编码RNA通过与PCR2结合进而调节组蛋白修饰复合物、激活EMT基因并诱导肾癌进展的分子机制。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的领域。以及肾癌治疗的潜在治疗靶点。