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

改变的 microRNA 作为肥胖相关女性癌症发病的生物标志物

• 批准号: 8626128
• 负责人: Mandi M Murph
• 金额: $ 42.68万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-06 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626128
• 关键词: Adipocytes; Affect; Animal Model; Apoptosis; Automobile Driving; BCL9 gene; Behavioral; Binding; Biological Markers; Blood Circulation; Body mass index; Breast; Cancer Cell Growth; Cell Proliferation; Cell secretion; Cells; Chromosome Arm; Coculture Techniques; Data; Dependency; Development; Development Plans; Diet; Disease; Early Diagnosis; Environmental Risk Factor; Enzymes; Epigenetic Process; Epithelial Cells; Etiology; Family; Family member; Feedback; Female; Functional RNA; Genetic; Goals; Growth Factor; Human; Knock-in Mouse; Lipids; Lysophosphatidic Acid Receptors; Lysophospholipids; Malignant Neoplasms; Malignant neoplasm of ovary; Measurable; Measures; Mediating; MicroRNAs; Microsomes; Modeling; Molecular; Mus; Obese Mice; Obesity; Obesity associated cancer; Oncogenic; Outcome; Ovarian; Ovary; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Plasma; Population; Predisposition; Premalignant; Prevention strategy; Proteins; Public Health; Publications; Receptor Activation; Research Proposals; Role; Signal Pathway; Signal Transduction; Specimen; Testing; Therapeutic; Tissues; Transcript; Transgenic Mice; Weight Gain; Wild Type Mouse; Woman; cancer cell; cancer prevention; cancer risk; carcinogenesis; extracellular; human DICER1 protein; improved; in vivo; inhibitor/antagonist; lysophosphatidic acid; malignant breast neoplasm; mortality; mouse model; novel; overexpression; paracrine; public health relevance; receptor; receptor expression; receptor function; small molecule; tumor; tumorigenesis; university student; vzg-1 Receptor

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.

虽然癌症是美国女性死亡的主要原因，但引发癌症的主要诱因是 未知，因此一些女性癌症仍然是特发性的，起源继续躲避 理解。对肿瘤发生的易感性可能是由非编码RNA的解除调控引起的， 因为这些小分子在细胞中起着很大的调节作用。这项研究的一个主要目标是 建议生成非编码RNA生物标记物，以帮助早期发现和预防 通过表现出易患恶性的迹象而患上癌症。为了实现这一目标，我们提出了一个 一种假说，即microRNAs(MiRNAs)的改变涉及推动 与肥胖相关的女性癌症，如乳腺癌和卵巢癌。这项研究的另一个主要目标 建议对所涉及的分子机制进行界定。使用迟发性肥胖的小鼠模型 这与饮食和导致随后的自发性癌症发展无关，我们计划测试 我们的中心假设：自体趋化因子诱导的致癌生长因子信号的增强 由溶血磷脂酸(LPA)介导，存在于脂肪细胞和癌前细胞中，并且是由LPA介导的 用于致癌。此外，一种分步机制导致自体趋化蛋白和LPA的改变。 脂肪细胞中受体的表达和功能，影响生长因子信号转导 并产生可测量的分泌的特定调控miRNAs的变化。我们 预测这种现象可以在血浆中量化，因为miRNAs稳定地分泌到 胞外外体、微体或与ArgAert蛋白结合。我们之前已经展示了miR- 30C-2-3P参与调控反馈环，以抑制由 LPA介导的受体激活。此外，MIR-30c-2-3p的表达和功能也异常。 许多卵巢癌细胞。我们预测miR-30c-2-3p(和miR-30家族成员)将是 在我们肥胖的小鼠模型中发生了可测量的变化，这是我们第一个特定目标的目标。我们的第二个 目的明确阶梯式分子机制，了解分子间的关系 在脂肪细胞和癌细胞之间，miR-30c-2-3p调节癌细胞的增殖。在……里面 我们的第三个具体目标是，我们试图量化健康人群中特定的miRNAs 以确定它们是否会因体重指数而改变，并可能 为易感性提供可测量的生物标记物。这些研究可以定义一个可识别的前驱 通过测量女性癌症发病前非编码RNA的调制情况。 表征导致肿瘤发生的分子机制和阶段性途径应 提高我们对与饮食无关的晚发型肥胖症如何推动癌症发展和 发现治疗调整的新机会。

项目成果

The Role of Fluorinated Alcohols as Mobile Phase Modifiers for LC-MS Analysis of Oligonucleotides.

• DOI: 10.1007/s13361-016-1500-3
• 发表时间: 2017-01
• 期刊: Journal of the American Society for Mass Spectrometry
• 影响因子: 3.2
• 作者: Basiri B;van Hattum H;van Dongen WD;Murph MM;Bartlett MG
• 通讯作者: Bartlett MG

Lysophosphatidic Acid Mediates Activating Transcription Factor 3 Expression Which Is a Target for Post-Transcriptional Silencing by miR-30c-2-3p.

溶血磷脂酸介导激活转录因子 3 表达，这是 miR-30c-2-3p 转录后沉默的靶标。

• DOI: 10.1371/journal.pone.0139489
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Nguyen,HaT;Jia,Wei;Beedle,AaronM;Kennedy,EileenJ;Murph,MandiM
• 通讯作者: Murph,MandiM

Assessing the Interplay between the Physicochemical Parameters of Ion-Pairing Reagents and the Analyte Sequence on the Electrospray Desorption Process for Oligonucleotides.

评估离子对试剂的物理化学参数与寡核苷酸电喷雾解吸过程中的分析物序列之间的相互作用。

• DOI: 10.1007/s13361-017-1671-6
• 发表时间: 2017-08
• 期刊: Journal of the American Society for Mass Spectrometry
• 影响因子: 3.2
• 作者: Basiri B;Murph MM;Bartlett MG
• 通讯作者: Bartlett MG

Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p.

• DOI: 10.1016/j.canlet.2018.05.037
• 发表时间: 2018-09-28
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Kuppa SS;Jia W;Liu S;Nguyen H;Smyth SS;Mills GB;Dobbin KK;Hardman WJ;Murph MM
• 通讯作者: Murph MM