Chemo-dietary prevention, miRNAs, epigenetic and prostate cancer

描述(申请人提供)：该项目的主要目标是研究饮食中的异黄酮如染料木素是否可以通过激活肿瘤抑制基因(MiRNAs)来抑制前列腺癌的生长。前列腺癌是美国最常见的男性恶性肿瘤，也是男性癌症死亡的第二大原因。这个项目的基本原理是，最近的研究表明，在体外和体内模型中，饮食对miRNAs的调节都有显著影响。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基因miRNAs，从而通过两种不同的途径抑制前列腺癌的进展。首先，金雀异黄素诱导的抑癌基因miRNAs通过与3‘端非翻译区(3’UTR)结合来抑制癌基因的表达。第二，金雀异黄素诱导的抑癌基因miRNAs可以通过与基因5‘上游区结合来激活抑癌基因的转录，或通过与5’端非翻译区(5‘UTR)结合来激活翻译。这个项目是新颖和及时的，因为金雀异黄素介导的肿瘤抑制因子miRNAs的激活在前列腺癌进展调控中的作用尚未被研究。我们还假设金雀异黄素介导的肿瘤抑制基因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。具体目的#1.验证金雀异黄素介导的肿瘤抑制基因激活与前列腺癌调控有关的假说。具体目的#2：验证DNA甲基化和组蛋白修饰是金雀异黄素介导的前列腺癌microRNAs激活的关键机制的假设。具体目标#3：测试金雀异黄素可以通过激活microRNAs在裸鼠模型中抑制前列腺癌生长的假设。影响：该项目将在前列腺癌管理领域提供一个新的范例，具有很高的影响力，因为饮食介导的肿瘤抑制因子miRNAs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.