Altered microRNA as a biomarker for the onset of obesity related womens cancers

虽然癌症是美国女性死亡的主要原因，触发器主要是 因此，一些女性的癌症仍然是特发性的，并且起源继续逃避。 认识对肿瘤发生的易感性可能是由非编码RNA的失调引起的， 因为这些小分子在细胞中具有很大的调节作用。这项研究的一个主要目标 一项建议是产生非编码RNA生物标志物，以帮助早期检测和预防 癌症通过指示恶性肿瘤的倾向。为了实现这一目标，我们提出了一个 一种假说，即microRNAs（miRNAs）的改变涉及驱动 与肥胖有关的女性癌症，如乳腺癌和卵巢癌。这项研究的另一个主要目标 建议是确定所涉及的分子机制。使用迟发性肥胖的小鼠模型 这与饮食无关，并导致随后的自发性癌症发展，我们计划测试 我们的中心假设：自分泌运动因子诱导的致癌生长因子信号转导增强 由溶血磷脂酸（LPA）介导的发生在脂肪细胞和癌前细胞中， 致癌作用。此外，一个逐步的机制导致自分泌运动因子和LPA的改变 受体的表达和功能，影响生长因子的信号传导， 在一些实施方案中，所述方法包括在细胞周围的细胞中检测细胞的生长，并产生分泌的特异性调节性miRNA的可测量的改变。我们 预测这种现象可以在血浆中定量，因为miRNA稳定地分泌到血浆中。 细胞外外来体、微粒体或结合Argonaut蛋白。我们之前已经证明了miR- 30 c-2- 3 p参与调节反馈环，以抑制致癌转录物， LPA介导的受体活化。此外，miR-30 c-2- 3 p表达和功能异常， 许多卵巢癌细胞我们预测miR-30 c-2- 3 p（和miR-30家族成员）将在 在我们的肥胖小鼠模型中发生了可测量的改变，这是我们第一个具体目标的目标。我们的第二 目的是确定逐步的分子机制，并了解分子关系 在脂肪细胞和癌细胞之间，miR-30 c-2- 3 p调节癌细胞增殖。在 我们的第三个具体目标是，我们试图量化健康人群中的特定miRNA 以确定它们是否因体重指数而改变， 为易感性提供可测量的生物标志物。这些研究可以确定一个可识别的前- 通过测量妇女癌症发病前非编码RNA的调节来确定病情。 肿瘤发生的分子机制和逐步途径的特征应 提高我们对与饮食无关的迟发性肥胖如何驱动癌症发展的理解， 发现治疗调节的新机会。

Although cancer is a leading cause of mortality for women in the U.S., the initiating triggers are mainly unknown, thus some women's cancers remain idiopathic and the origins continue to evade understanding. Susceptibility to oncogenesis may be caused by deregulation of non-coding RNAs, since these small molecules have large regulatory roles in the cell. A major goal of this research proposal is to generate non-coding RNA biomarkers to assist in the early detection and prevention of cancer through the indication of a predisposition to malignancy. To achieve this goal, we propose a hypothesis whereby alterations of microRNAs (miRNAs) are implicated in driving the development of obesity-related women's cancers, such as breast and ovary. Another major goal of this research proposal is to define the molecular mechanism involved. Using a mouse model of late-onset obesity that is unrelated to diet and results in subsequent spontaneous cancer development, we plan to test our central hypothesis: autotaxin-induced enhancement of oncogenic growth factor signaling mediated by lysophosphatidic acid (LPA) occurs in adipocytes and pre-malignant cells and is causal for carcinogenesis. Further, a stepwise mechanism results in an alteration of autotaxin and LPA receptor expression and function in adipocytes, which affects growth factor signaling to the surrounding cells and yields a measurable alteration of specific regulatory miRNAs secreted. We predict this phenomenon can be quantified in plasma since miRNAs are stably secreted into extracellular exosomes, microsomes or bound to Argonaut proteins. We have previously shown miR- 30c-2-3p participates in a regulatory feedback loop to inhibit oncogenic transcripts that are initiated by LPA-mediated receptor activation. Moreover, miR-30c-2-3p expression and function is abnormal in many ovarian cancer cells. We predict miR-30c-2-3p (and the miR-30 family members) will be measurably altered in our obese mouse model, which is the goal of our first specific aim. Our second aim seeks to define the stepwise molecular mechanism and understand the molecular relationship between adipocytes and cancer cells, whereby miR-30c-2-3p regulates cancer cell proliferation. In our third specific aim, we seek to quantify specific miRNAs in an otherwise healthy human population in order to determine whether they are altered as a consequence of body mass index and could provide a measurable biomarker for susceptibility. These studies could define an identifiable pre- condition by measuring modulations in non-coding RNA prior to the onset of women's cancer. Characterization of the molecular mechanism and stepwise pathway leading to tumorigenesis should improve our understanding of how diet-unrelated, late-onset obesity drives cancer development and uncover novel opportunities for therapeutic modulation.