MODULATION OF IGF-II IMPRINTING IN THE AGING PROSTATE

前列腺癌的三个重要特征将在本提案中讨论，这将提高我们对前列腺癌发展的危险因素的理解。这些特征包括：1)前列腺癌的多灶性，这意味着癌症易感性的普遍或局部变化；2)前列腺癌发展的年龄依赖性；3)胰岛素样生长因子轴在衰老相关和遗传相关癌症中的重要作用。IGF-II是一种自身旁分泌生长刺激因子，是癌症发展的重要正调节因子。我们提供的初步证据表明，印迹丧失（LOI），或双等位基因表达，是一种与年龄相关的特异性表观遗传改变，发生在人类前列腺外周。IGF-II在成人组织中的印记通常是维持的，而LOI是前列腺癌的共同特征。由于DNA甲基化是IGF-II印迹的主要决定因素，我们预计甲基化的变化将与印迹状态的改变有关。我们的假设有待验证，IGF-II基因组印记的丢失是前列腺上皮细胞中与年龄相关的事件，可能通过DNA甲基化的变化来调节。在特异性目标1中，我们将确定衰老小鼠前列腺中是否发生IGF-II的LOI。在特异性目标2中，将评估加速DNA甲基化丢失对小鼠和体外人模型印迹的影响。特异性目的3将确定这些机制和/或其他机制是否导致衰老过程中IGF-II表达的增加。这一建议意义重大且新颖，因为它有能力在衰老过程、饮食和体内前列腺癌发生之间提供关键的表观遗传联系。我们希望确定IGF-II印记是否随着年龄的增长而改变，以及改变的DNA甲基化是否是这一现象的潜在机制。即使在不太可能发生的情况下，IGF-II在前列腺癌的发生中只起很小的作用，这一建议也代表了一种新的、重要的方法来评估表观遗传场的变化，这可能解释前列腺癌的年龄、器官和饮食相关的特异性。

Three important features of prostate cancer will be addressed in the present proposal that will improve our understanding of risk factors for the development of prostate cancer. These features include: i) the multifocality of prostate cancer which implicates a generalized or field change in cancer susceptibility, ii) the age-dependence of prostate cancer development, and iii) the important role of the Insulin-like Growth Factor Axis in both aging-related and genetic-related cancers. IGF-II is an auto-paracrine growth stimulator that is an important positive modulator of cancer development. We provide preliminary evidence that a loss of imprinting (LOI), or biallelic expression, is an age-related specific epigenetic alteration that occurs in the peripheral prostate of the human. The imprinting of IGF-II in adult tissues is typically maintained and LOI is a common attribute of prostate cancers. Since DNA methylation is a major determinant of IGF-II imprinting we would anticipate that changes in methylation would be associated with altered imprinting status. It is our hypothesis to be tested that a loss of genomic imprinting in IGF-II is an age-related event in prostate epithelial cells and may be modulated by changes in DNA methylation. In Specific Aim 1, we will determine if a LOI of IGF-II occurs in the aging mouse prostate. In Specific Aim 2, the impact of accelerating DNA methylation loss on imprinting in mouse and an in vitro human model will be assessed. Specific Aim 3 will determine whether these mechanisms, and/or others, engender the increase in IGF-II expression seen in aging. This proposal is significant and novel in that it has the ability to provide a critical epigenetic link between the aging process, diet and prostate carcinogenesis in vivo. We expect to determine whether IGF-II imprinting is altered with aging and whether altered DNA methylation is an underlying mechanism for this. Even in the unlikely event the IGF-II plays only a minor role in prostate carcinogenesis, this proposal represents a novel and important methodological approach to evaluating epigenetic field changes that may explain the age-, organ- and diet-related specificity of prostate cancer.