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Genistein and chemotherapy of kidney cancer

金雀异黄素与肾癌化疗

基本信息

批准号：
9336847
负责人：
Soichiro Yamamura
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：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336847
关键词：
Animal Model Animals Apoptosis Binding Biological Assay Biological Markers Cancer Model Cancer Patient Cancer cell line Cell Proliferation Clinical Complex Data Diet Disease Epithelial Flow Cytometry Genes Genetic Markers Genistein Goals Growth Histones Human Immunologic Deficiency Syndromes In Situ Hybridization In Vitro Incidence Injectable Injection of therapeutic agent Intervention Isoflavones Kidney Liver Lung Malignant Neoplasms Mediating Mesenchymal MicroRNAs Molecular Molecular Mechanisms of Action Monitor Mus NOD/SCID mouse Neoplasm Metastasis Oncogenic Organ Outcome Pathway interactions Polycomb Prevention Protocols documentation RNA Renal Cell Carcinoma Renal carcinoma Risk Assessment Series Techniques Testing Therapeutic Agents Time Tissues Transcriptional Regulation Tumor Suppressor Genes Tumor Suppressor Proteins Untranslated RNA animal imaging base bone cancer cell capsule chemotherapy clinically significant experimental study gene repression histone modification imaging system in vitro Model in vivo in vivo Model innovation lymph nodes migration mouse model novel novel strategies predict clinical outcome prognostic public health relevance screening transcription factor tumor tumor growth tumor progression

项目摘要

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.

描述（由申请人提供）：肾细胞癌（RCC）是最常见的恶性肿瘤之一，2014年新发肾细胞癌病例超过30，000例，在过去二十年中，该疾病的发病率增加了2 - 3倍。其理由是，多项研究表明染料木黄酮（膳食异黄酮）在各种体外和体内模型中抑制肾癌进展。然而，染料木黄酮作用的基本分子机制尚未在肾癌中研究。在这方面，最近的研究表明，饮食在各种动物模型中诱导非编码RNA的改变。该项目的主要目标是研究染料木黄酮通过抑制致癌长非编码RNA HOTAIR而发挥作用的基本机制，HOTAIR反过来调节组蛋白修饰复合物，抑制上皮-间充质转化（EMT）途径，并使用体外和体内模型抑制肾癌进展。该项目具有新颖性和临床意义，因为此类研究在肾癌中缺乏。我们假设HOTAIR与多梳抑制复合物2（PRC2）结合，诱导组蛋白修饰，并激活EMT途径基因，导致肾癌进展和转移。基于我们的初步数据，肾癌细胞系和人肾癌组织表达高水平的HOTAIR，染料木素抑制HOTAIR表达。我们推测染料木黄酮激活的miR-141将抑制HOTAIR、EMT通路基因和肾癌的进展和转移。我们还假设致癌HOTAIR的高表达和miR-141的低表达可用作遗传生物标志物，以帮助预测哪些局部肾癌可能进展、转移并需要积极的临床干预。为了验证这些假设，我们将追求以下具体目标。具体目标#1。研究染料木黄酮通过抑制致癌HOTAIR、与PRC2结合、激活肿瘤抑制基因和抑制EMT途径基因来抑制肾癌生长的基本机制。具体目标#2。在免疫缺陷小鼠模型中检验染料木黄酮可通过抑制致癌HOTAIR及其与多梳抑制复合物2（PRC2）的结合来抑制肾癌生长的假设。具体目标#3。分析HOTAIR和miR-141表达是否可用作遗传生物标志物，以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HOTAIR及其与PRC2的结合来研究染料木黄酮作用的新颖独特的分子机制，PRC2调节组蛋白修饰，抑制EMT途径并抑制肾癌进展。该项目的完成将为肾癌的治疗提供新的策略。