Chemo-dietary prevention, miRNAs, epigenetic and prostate cancer

化学饮食预防、miRNA、表观遗传和前列腺癌

• 批准号: 8149764
• 负责人: RAJVIR DAHIYA
• 金额: $ 46.14万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-06 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8149764
• 关键词: 3' Untranslated Regions; 5' Untranslated Regions; Address; Apoptosis; Binding; Biological Assay; Cancer Etiology; Cell Cycle; Cell Proliferation; Cessation of life; CpG Islands; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; DNA Sequence; DNMT3B gene; DNMT3a; Data; Diet; Drug toxicity; Epigenetic Process; Flow Cytometry; Future; Gene Targeting; Genes; Genetic Transcription; Genistein; Goals; Growth; Histologic; Histone Acetylation; In Vitro; Isoflavones; Literature; Luciferases; Malignant neoplasm of prostate; Mediating; Messenger RNA; Methods; Methylation; MicroRNAs; Molecular; Monitor; Mus; Neoplasm Metastasis; Nude Mice; Oncogenes; Organ; PC3 cell line; Pathway interactions; Prevention; Promoter Regions; Prostate; Prostatic Neoplasms; Proteins; Publishing; Regulation; Repression; Role; Second Primary Neoplasms; Series; Techniques; Testing; Time; Translations; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Xenograft procedure; base; bone; cancer cell; cell growth; chromatin remodeling; feeding; histone modification; in vivo Model; lymph nodes; male; men; migration; mouse model; novel; novel strategies; research study; sodium bisulfite; tumor progression

DESCRIPTION (provided by applicant): The main goal of this project is to investigate whether dietary isoflavones such as genistein can inhibit prostate cancer growth through activation of tumor suppressor microRNAs (miRNAs) using both in vitro and in vivo models. Prostate cancer is the most common male malignancy and the second leading cause of cancer death among men in the United States. The rationale for this project is that recent studies have shown significant effects of diet on modulation of miRNAs using both in vitro and in vivo models. Based on our preliminary data and published literature, we hypothesize that genistein can activate a set of tumor suppressor miRNAs thereby inhibiting prostate cancer progression through two different pathways. First, genistein induced tumor suppressor miRNAs can repress oncogene expression by binding to the 3' untranslated region of mRNA (3'UTR). Second genistein induced tumor suppressor miRNAs can activate the transcription of tumor suppressor genes by binding to the 5' upstream region of the gene or activate translation by binding to the 5' untranslated region of mRNA (5'UTR). This project is novel and timely because the roles of genistein mediated activation of tumor suppressor miRNAs in the regulation of prostate cancer progression have not been investigated. We also hypothesize that the molecular mechanism of genistein's mediated activation of tumor suppressor miRNAs are through epigenetic pathways. These hypotheses will be tested by pursuing the following three specific aims. Specific Aim # 1. To test the hypothesis that genistein mediated activation of tumor suppressor microRNAs are involved in the regulation of prostate cancer. Specific Aim # 2: To test the hypothesis that DNA methylation and histone modifications are the key mechanisms of genistein mediated activation of microRNAs in prostate cancer. Specific Aim # 3: To test the hypothesis that genistein can suppress prostate cancer growth in a nude mouse model through activation of microRNAs. Impact: The project will provide a novel paradigm with high impact in the field of management of prostate cancer since dietary mediated activation of tumor suppressor miRNAs and their roles in the inhibition of prostate cancer progression have never been investigated. Successful accomplishment of these experiments will provide novel strategies for the treatment of prostate cancer. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most common male malignancy and the second leading cause of cancer death among men in the United States. The rationale for this project is that recent studies have shown significant effects of diet on modulation of miRNAs using both in vitro and in vivo models. Based on our preliminary data and published literature, we hypothesize that genistein can activate a set of tumor suppressor miRNAs thereby inhibiting prostate cancer progression through different pathways. The major barrier to progress in the management of prostate cancer is the high toxicity of the drugs currently in use. The present proposal will address this problem by investigating the use of dietary methods for the management of prostate cancer in both in vitro and in vivo models. We have proposed a series of experiments to investigate the role of genistein in the regulation of prostate cancer progression through modulation of tumor suppressor miRNAs.

描述（由申请人提供）：该项目的主要目标是利用体外和体内模型研究膳食异黄酮（例如染料木黄酮）是否可以通过激活肿瘤抑制微小RNA（miRNA）来抑制前列腺癌的生长。前列腺癌是最常见的男性恶性肿瘤，也是美国男性癌症死亡的第二大原因。该项目的基本原理是，最近的研究表明饮食对体内和体外模型的 miRNA 调节有显着影响。根据我们的初步数据和已发表的文献，我们假设金雀异黄素可以激活一组肿瘤抑制 miRNA，从而通过两种不同的途径抑制前列腺癌的进展。首先，金雀异黄素诱导的肿瘤抑制 miRNA 可以通过结合 mRNA 的 3' 非翻译区 (3'UTR) 来抑制癌基因的表达。第二个金雀异黄素诱导的肿瘤抑制 miRNA 可以通过与基因的 5' 上游区域结合来激活肿瘤抑制基因的转录，或通过与 mRNA 的 5' 非翻译区 (5'UTR) 结合来激活翻译。该项目是新颖且及时的，因为金雀异黄素介导的肿瘤抑制 miRNA 激活在前列腺癌进展调节中的作用尚未得到研究。我们还假设金雀异黄素介导的抑癌 miRNA 激活的分子机制是通过表观遗传途径。这些假设将通过追求以下三个具体目标来检验。具体目标#1. 检验金雀异黄素介导的肿瘤抑制 microRNA 的激活参与前列腺癌的调节这一假设。具体目标#2：检验 DNA 甲基化和组蛋白修饰是前列腺癌中金雀异黄素介导 microRNA 激活的关键机制这一假设。具体目标#3：测试金雀异黄素可以通过激活 microRNA 在裸鼠模型中抑制前列腺癌生长的假设。影响：该项目将为前列腺癌的治疗领域提供一个具有重大影响的新范例，因为饮食介导的肿瘤抑制 miRNA 的激活及其在抑制前列腺癌进展中的作用从未被研究过。这些实验的成功完成将为前列腺癌的治疗提供新的策略。 公共卫生相关性：前列腺癌是最常见的男性恶性肿瘤，也是美国男性癌症死亡的第二大原因。该项目的基本原理是，最近的研究表明饮食对体内和体外模型的 miRNA 调节有显着影响。根据我们的初步数据和已发表的文献，我们假设金雀异黄素可以激活一组肿瘤抑制 miRNA，从而通过不同的途径抑制前列腺癌的进展。前列腺癌治疗进展的主要障碍是目前使用的药物的高毒性。目前的提案将通过研究在体外和体内模型中使用饮食方法来管理前列腺癌来解决这个问题。我们提出了一系列实验来研究金雀异黄酮通过调节肿瘤抑制 miRNA 来调节前列腺癌进展的作用。