Molecular biomarkers for kidney cancer prognosis using non-coding RNAs

 描述(申请人提供)：这个项目的主要目标是开发基于长的非编码RNA分析的预后生物标记物，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记物或方法来预测肾癌的临床结果。为了解决这个问题，我们将调查是否可以使用长非编码RNA(LncRNAs)作为遗传生物标记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。第一种假设认为，癌基因lncRNAs HOTAIR和MALAT1及其结合的miRNAs在不同分期和分级的肾癌中的差异表达可能是判断肾癌预后的生物标志物。第二个假设是，通过体外和体内模型，通过siRNAs抑制致癌基因MALAT1和HOTAIR或激活它们结合的miRNAs将抑制肾癌的生长和进展。第三种假设认为，致癌的长非编码RNA HOTAIR和MALAT1的作用机制是通过与多梳抑制复合体2[PRC2(EZH2/SUZ12/EED)]结合，进而调节组蛋白修饰复合体，激活上皮-间充质转化途径基因(蜗牛、鼻涕、扭曲、波形蛋白、ZEB1和ZEB2)，从而诱导肾癌的进展。为了解决这些假设，我们提出了以下具体目标。具体目的1.研究MALAT1、HOTAIR及其调控miRNAs是否为有助于肾癌临床评估的遗传生物标记物。具体目的#2.利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。具体目的#3.研究MALAT1和HOTAIR在肾癌生长和发展中的分子作用机制。影响：该项目具有很高的影响力，因为它将调查非编码RNA作为肾癌风险评估的遗传生物标记物的作用。我们将使用体外和体内模型来研究非编码RNA在肾癌中的功能意义。我们还将研究非编码RNA与PCR2结合的分子作用机制，PCR2反过来调节组蛋白修饰复合体，激活EMT基因，并诱导肾癌进展。提出的概念、方法和技术将推动非编码RNA作为遗传生物标记物和肾癌治疗潜在治疗靶点的领域。

 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.