Chemo-dietary prevention, miRNAs, epigenetic and prostate cancer

描述（由申请人提供）：本项目的主要目标是研究膳食黄酮如染料木黄酮是否可以通过体外和体内模型激活肿瘤抑制微RNA（miRNA）来抑制前列腺癌生长。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，使用体外和体内模型，饮食对miRNAs的调节具有显著影响。基于我们的初步数据和已发表的文献，我们假设染料木黄酮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，染料木黄酮诱导的肿瘤抑制miRNAs可以通过与mRNA的3'非翻译区（3'UTR）结合来抑制癌基因的表达。第二，染料木黄酮诱导的肿瘤抑制miRNAs可以通过结合到基因的5'上游区域来激活肿瘤抑制基因的转录，或者通过结合到mRNA的5'非翻译区（5'UTR）来激活翻译。这个项目是新颖的和及时的，因为染料木黄酮介导的肿瘤抑制miRNA的激活在前列腺癌进展的调节中的作用还没有被研究。我们还推测染料木黄酮介导的肿瘤抑制miRNAs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。验证染料木黄酮介导的肿瘤抑制microRNA的激活参与前列腺癌的调控这一假设。具体目标2：验证DNA甲基化和组蛋白修饰是染料木黄酮介导的前列腺癌microRNA激活的关键机制的假设。具体目标#3：在裸鼠模型中检验染料木黄酮可通过激活microRNA抑制前列腺癌生长的假设。影响：该项目将提供一种在前列腺癌管理领域具有高度影响力的新范式，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。

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.