Autoantibodies against micro RNA for Early Cancer Detection

用于早期癌症检测的微小 RNA 自身抗体

• 批准号: 8874017
• 负责人: Gang Zeng
• 金额: $ 19.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874017
• 关键词: Address; Age; Apoptosis; Autoantibodies; Biological Assay; Biological Markers; Cancer Patient; Cell Cycle; Cells; Clinical; Collaborations; Data; Dendritic Cells; Development; Diagnosis; Early Diagnosis; Environment; Equilibrium; Event; F-Actin; Gene Expression Regulation; Genetic Transcription; Goals; Human; Human Genome; Immune; Immune response; Immune system; Immunocompetence; Immunoglobulin G; In Vitro; Individual; Indolent; Inflammation; Inflammatory; Knowledge; Laboratories; Light; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Metabolism; Methodology; Methods; MicroRNAs; Molecular Weight; Mutagenesis; Non-Malignant; Operative Surgical Procedures; Patients; Play; Proteins; RNA; Reporting; Risk; Role; Sampling; Screening for Prostate Cancer; Screening for cancer; Sensitivity and Specificity; Serum; Signal Transduction; Signaling Molecule; Specificity; Staging; Symptoms; Testing; Time; Tissues; Translating; Tumor Antigens; Up-Regulation; arm; base; cancer type; chemokine; cohort; cost; cytokine; differential expression; extracellular; immunogenic; immunogenicity; inhibitor/antagonist; male; monocyte; novel; outcome forecast; peripheral blood; prototype; public health relevance; racial and ethnic; response; success; tool; tumor; tumor microenvironment; tumorigenesis

 DESCRIPTION (provided by applicant): In parallel with proteins, microRNA (miRNA) represents an entirely new domain of functional molecules encoded by the human genome. Besides their bona fide functions to regulate RNA transcriptions inside the cell, mature miRNA are found in the tumor environment and the peripheral blood, and interact with the innate immune system as extracellular signaling molecules. These cancer-associated miRNA are potentially immunogenic considering they are differentially expressed between cancer and healthy tissues, stable, and have molecular weights around 7 kDa. In our preliminary studies, cancer-associated miRNA were screened for activating human dendritic cells (DC) based on morphological changes, maturation status and secretion of pro-inflammatory cytokine/chemokine(s). Activation of human DC was found to coincide with immunological responses against a couple of cancer-associated miRNA detected preferentially in patients with prostate and lung cancer but not non-malignant donors. As a result, a sensitive and robust method for quantifying autoantibody (Ab) responses against miRNA has been developed in our laboratory with the potential to become novel biomarkers for a number of cancers. The hypothesis for this study is that some cancer-associated miRNA may function as "danger signals" and induce IgG Ab responses as a result of cancer manifestation. IgG Ab responses against cancer-associated miRNA are thus attractive cancer-specific biomarkers. To test the above hypothesis in light of the preliminary data, we propose to screen cancer-associated miRNA and validate the specificity of IgG Ab responses against cancer-associated miRNA determinants (aim 1). We will retrospectively assess Ab responses against cancer-associated miRNA alone or as part of the "A+PSA" platform assay for early detection of prostate cancer. This will be conducted in collaboration with San Antonio Center of Biomarkers of Risk for Prostate Cancer using a large cohort of prostate cancer patients as well as age- and racial/ethnic background-matched healthy males (aim 2). Due to the limited sensitivity and specificity for miR-17 and -21-sepcific autoAb alone, this study is not intended to develop ready-to-use biomarkers; it rather opens doors for new biomarkers centered on miRNA-specific autoAb. Furthermore, owning to the highly important roles miRNA play in regulating oncogenesis, cell cycle, apoptosis, inflammation, and other hallmarks of human cancers, immune responses against cancer-associated miRNA have great promise as tools to aid early detection, diagnosis, and prognosis of multiple human cancers.

 描述（由申请人提供）：与蛋白质平行，微小RNA（miRNA）代表了由人类基因组编码的功能分子的全新结构域。成熟的miRNA除了具有调节细胞内RNA转录的功能外，还存在于肿瘤环境和外周血中，并作为细胞外信号分子与先天免疫系统相互作用。考虑到这些癌症相关的miRNA在癌症和健康组织之间差异表达、稳定并且具有约7 kDa的分子量，它们具有潜在的免疫原性。在我们的初步研究中，基于形态学变化、成熟状态和促炎细胞因子/趋化因子的分泌，筛选用于激活人树突状细胞（DC）的癌症相关miRNA。发现人DC的激活与针对优先在前列腺癌和肺癌患者中检测到的一对癌症相关miRNA的免疫应答相一致，而非恶性供体。因此，我们的实验室已经开发出一种灵敏而稳健的方法来定量针对miRNA的自身抗体（Ab）反应，该方法有可能成为许多癌症的新型生物标志物。 这项研究的假设是，一些癌症相关的miRNA可能作为“危险信号”发挥作用，并诱导IgG抗体反应作为癌症表现的结果。因此，针对癌症相关miRNA的IgG Ab应答是有吸引力的癌症特异性生物标志物。为了根据初步数据测试上述假设，我们提出筛选癌症相关miRNA并验证IgG Ab应答对癌症相关miRNA决定簇的特异性（目的1）。我们将回顾性评估单独或作为“A+PSA”平台测定的一部分针对癌症相关miRNA的Ab应答，用于前列腺癌的早期检测。这将与圣安东尼奥前列腺癌风险生物标志物中心合作，使用大型前列腺癌患者队列以及年龄和种族/民族背景匹配的健康男性（目的2）。 由于单独使用miR-17和miR-21特异性autoAb的灵敏度和特异性有限，本研究不旨在开发即用型生物标志物;而是为以miRNA特异性autoAb为中心的新生物标志物打开了大门。此外，由于miRNA在调节肿瘤发生、细胞周期、细胞凋亡、炎症和人类癌症的其他标志中起着非常重要的作用，针对癌症相关miRNA的免疫应答作为帮助多种人类癌症的早期检测、诊断和预后的工具具有很大的前景。