Genistein and chemotherapy of kidney cancer

 描述(申请人提供)：肾细胞癌(RCC)是最常见的恶性肿瘤之一，2014年有超过30,000例新发肾细胞癌病例，在过去20年中，该疾病的发病率增加了2-3倍。其基本原理是，几项研究表明，金雀异黄素(膳食异黄酮)在不同的体外和体内模型中抑制肾癌的进展。然而，金雀异黄素在肾癌中作用的基本分子机制尚未被研究。在这方面，最近的研究表明，饮食可以在各种动物模型中诱导非编码RNA的变化。本项目的主要目的是通过抑制致癌的长非编码RNA HOTAIR，进而调节组蛋白修饰复合体，抑制上皮-间充质转化(EMT)途径，并通过体外和体内模型研究染料木素的基本作用机制。这项拟议的项目具有新颖性和临床意义，因为这类研究缺乏对肾癌的研究。我们的假设是HOTAIR与多梳抑制复合体2(PRC2)结合，诱导组蛋白修饰，并激活导致肾癌进展和转移的EMT途径基因。根据我们的初步数据，肾癌细胞株和人肾癌组织表达高水平的HOTAIR，而金雀异黄素抑制HOTAIR的表达。我们推测金雀异黄素激活的miR-141将抑制HOTAIR、EMT通路基因和肾癌的进展和转移。我们还假设，癌基因HOTAIR的高表达和miR-141的低表达可以作为遗传生物标记物来帮助预测哪些局部肾癌可能进展、转移和需要积极的临床干预。为了检验这些假设，我们将追求以下具体目标。具体目的1.利用体外模型研究染料木素通过抑制致癌基因HOTAIR、与PRC2结合、激活抑癌基因和抑制EMT通路基因抑制肾癌生长的基本机制。具体目的#2.通过抑制致癌基因HOTAIR及其与多梳抑制复合体2(PRC2)的结合，验证金雀异黄素可以通过抑制致癌基因HOTAIR抑制免疫缺陷小鼠模型的肾癌生长的假设。具体目的#3.分析HOTAIR和miR-141的表达是否可以作为遗传生物标记物，帮助预测哪些局部肾癌可能进展和转移。影响：该项目具有很高的影响力，因为它将通过抑制致癌的HOTAIR及其与PRC2的结合来研究染料木素作用的新颖和独特的分子机制，组蛋白修饰、抑制EMT途径和抑制肾癌进展。该项目的完成将为肾癌的治疗提供新的策略。

 DESCRIPTION (provided by applicant): Renal cell carcinoma (RCC) is one of the most common malignancies with more than 30,000 new cases of renal cell carcinoma in 2014 and the incidence of this disease has increased by 2-3 folds over the last two decades. The rationale is that several studies have shown that genistein (dietary isoflavone) inhibits kidney cancer progression in various in vitro and in vivo models. However, the basic molecular mechanisms of genistein action have not been investigated in kidney cancer. In this regard, recent studies have shown that diet induces alterations in non-coding RNAs in various animal models. The main goal of this project is to investigate the basic mechanisms of genistein action through suppression of oncogenic long non-coding RNA HOTAIR that in turn modulates histone modification complexes, suppresses the epithelial-mesenchymal transition (EMT) pathway and represses kidney cancer progression using both in vitro and in vivo models. The proposed project is novel and clinically significant since such studies are lacking in kidney cancer. We hypothesis is that HOTAIR binds to the polycomb repressive complex 2 (PRC2), induces histone modification, and activates EMT pathway genes leading to kidney cancer progression and metastasis. Based on our preliminary data, kidney cancer cell lines and human kidney cancer tissues express high levels of HOTAIR and genistein inhibits HOTAIR expression. We hypothesize that genistein activated miR-141 will inhibit HOTAIR, EMT pathway genes and kidney cancer progression and metastasis. We also hypothesize that high expression of oncogenic HOTAIR and low expression of miR-141 can be used as genetic biomarkers to help predict which localized kidney cancers are likely to progress, metastasize and require aggressive clinical intervention. To test these hypotheses, we will pursue the following specific aims. Specific Aim # 1. Investigate the basic mechanisms of genistein action in inhibition of kidney cancer growth through suppression of oncogenic HOTAIR, it's binding to PRC2, activation of tumor suppressor genes and repression of EMT pathway genes using in vitro models. Specific Aim # 2. Test the hypothesis that genistein can inhibit kidney cancer growth in an immunodeficiency mouse model through suppression of oncogenic HOTAIR and it's binding to polycomb repressive complex 2 (PRC2). Specific Aim # 3. Analyze whether HOTAIR and miR-141 expression can used as genetic biomarkers to help predict which localized kidney cancers are likely to progress and metastasize. Impact: This project has high impact because it will investigate a novel and unique molecular mechanism of genistein action through suppression of oncogenic HOTAIR and its binding to PRC2 that modulates histone modification, suppression of the EMT pathway and represses kidney cancer progression. Accomplishment of this project will provide novel strategies for the management of kidney cancer.