Persistent microRNA changes in serum of cancer-free breast cancer patients

无癌乳腺癌患者血清中持续的 microRNA 变化

• 批准号: 8240038
• 负责人: Harikrishna Nakshatri
• 金额: $ 16.75万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-09 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240038
• 关键词: Accounting; Adipose tissue; Anabolism; Animal Model; Animals; Biological Markers; Blood; Blood Circulation; Breast Cancer Cell; Breast Cancer Treatment; Cancer Control; Cancer Etiology; Cancer Patient; Cancer Survivor; Cell Count; Cell Death; Cells; Chronic; Clinical; Complex; DNA Methylation; DNA-Directed RNA Polymerase; Development; Disease; Distant; Drops; Epigenetic Process; Estrogen receptor negative; Estrogen receptor positive; Excision; Extracellular Space; Functional RNA; Gene Expression; Genes; Genetic Polymorphism; Genetic Transcription; Goals; Health; Histones; IL6 gene; Immune response; Inflammation; Interleukin-6; Lead; Lipids; Liver; Liver diseases; Long-Term Effects; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Mediating; MicroRNAs; Mouse Mammary Tumor Virus; Mus; Neoadjuvant Therapy; Normal tissue morphology; Nucleic Acid Regulatory Sequences; Operative Surgical Procedures; Organ; Patients; Pattern; Persons; Play; RNA; RNA Polymerase II; RNA Polymerase III; Recording of previous events; Rest; Role; Serum; Signal Pathway; Small RNA; Source; Structure of parenchyma of lung; Testing; Tumor Burden; Tumor-Derived; U6 small nuclear RNA; Xenograft procedure; arm; base; cancer cell; cytokine; healthy volunteer; histone modification; malignant breast neoplasm; minimally invasive; neoplastic cell; outcome forecast; promoter; public health relevance; regenerative; research study; tumor; tumor progression

DESCRIPTION (provided by applicant): The development of clinically applicable biomarkers for cancer, particularly minimally invasive biomarkers, has been an insurmountable challenge for a number of years. Recent discovery of circulating microRNAs provided some hope; these microRNAs have been suggested to be biomarkers of breast, lung, and prostate cancer. The source of these circulating microRNAs is unknown but is believed to be derived from cancer either through secreted exosomes or released by dying cancer cells. Intriguingly, the levels of several microRNAs are lower in the serum of cancer patients compared to healthy suggesting that cancer is either causing destruction of the adjoining normal tissues from which these microRNAs are normally secreted or it is influencing the expression and secretion of these microRNAs from distant organs. Our recent studies support the latter possibility; serum from breast cancer patients, who are clinically disease-free, displayed elevated levels of miR-451 and miR-101 but lower levels of miR-370, miR-574-3p, miR-342-3p, and miR-197. Additionally, serum from patients contained elevated levels of U6 and 5S, which are small RNAs transcribed by RNA polymerase III. The following hypotheses will be tested in this proposal: Chronic inflammation-like condition in cancer patients lead to permanent changes in microRNA/small RNA expression in distant organs, particularly in organs with regenerative capacity such as liver. Cancer or host-response to cancer causes elevated levels of circulating cytokines such as interleukin 6 (IL-6), which may mediate the long-term effects of cancer on microRNA expression in distant organs. Consequently, distinct microRNA and U6 RNA levels persist in the serum of cancer patients even after these patients are clinically free of the disease. Experiments described in two specific aims will test the above hypotheses: I) Determine whether genes corresponding to microRNAs/small RNA differentially expressed in the serum of cancer bearing animals show altered expression, histone modifications, and RNA polymerase occupancy in liver and lungs. The animal models of breast cancer including MMTV-PyMT, MMTV-neu and xenografts with ER1- positive and ER1-negative breast cancer cells along with appropriate controls will be used to measure serum microRNA profile and cancer-associated changes in microRNA, U6 and 5S expression in liver and lungs. Recruitment of modified histones and RNA polymerase II/III to regulatory regions of U6, 5S, and select microRNA genes in liver and lungs will be measured in control and cancer bearing animals. Serum will be analyzed for mouse IL-6. II) Investigate prospectively whether serum U6, 5S and select miRNA levels change during breast cancer treatment. Serum from breast cancer patients prior to starting neoadjuvant therapy, immediately after completing therapy but before surgery, and after surgery will be examined for U6, 5S RNA and select microRNAs. If cancer is the primary source of the above microRNA/ small RNAs in the serum, their levels should drop after neoadjuvant therapy and/or surgery. If specific microRNA is host -derived and changes in its expression in distant organ is permanent, therapy should not influence its expression. Long-term goal is to determine cancer-induced collateral damage to other organs and how this damage may influence overall health of cancer patients. PUBLIC HEALTH RELEVANCE: This proposal will examine whether microRNAs and small RNAs detected in the serum of breast cancer patients originate from cancer or from the distant organs. It is likely that the chronic inflammation-like condition in cancer patients may cause permanent gene expression changes in liver and lungs, which leads to altered levels of serum microRNAs and small RNAs. The circulating microRNAs may be the invisible long-arm of cancer that reaches distant organs as circulating microRNAs can fuse with heterotypic cells and influence gene expression.

描述（由申请人提供）：多年来，临床适用的癌症生物标志物（尤其是微创生物标志物）一直是无法克服的挑战。最近发现的循环microRNA提供了一些希望。这些microRNA被认为是乳腺癌，肺和前列腺癌的生物标志物。这些循环microRNA的来源尚不清楚，但据信是通过分泌的外泌体从癌症中衍生而来的，或者通过垂死的癌细胞释放。有趣的是，与健康相比，癌症患者血清中几种microRNA的水平较低，这表明癌症要么会造成这些microRNA通常是分泌的相邻正常组织的破坏，要么在影响远处器官的这些microRNA的表达和分泌。我们最近的研究支持后一种可能性。乳腺癌患者的血清无临床病，显示出miR-451和miR-101的水平升高，但miR-370，miR-574-3p，miR-342-3p和miR-197水平较低。此外，来自患者的血清含有升高的U6和5s，这些含量是由RNA聚合酶III转录的小RNA。 该建议将在癌症患者中进行以下假设：慢性炎症状态导致远处器官中的microRNA/小RNA表达永久变化，尤其是在具有再生能力的器官（如肝脏）中。癌症或对癌症的宿主反应会导致循环细胞因子水平升高，例如白介素6（IL-6），这可能介导癌症对远方器官microRNA表达的长期影响。因此，即使这些患者在临床上没有疾病之后，癌症患者的血清血清中有明显的microRNA和U6 RNA水平仍然存在。在两个特定目标中描述的实验将检验上述假设：i）确定在癌症轴承动物血清中差异表达的microRNAS/小RNA的基因是否显示出肝脏和肺中RNA聚合酶占用率的改变，组蛋白修饰和RNA聚合酶占有率。包括MMTV-PYMT，MMTV-NEU和异种移植物具有ER1-阳性和ER1阴性乳腺癌细胞以及适当的对照组的动物模型，将用于测量肝脏和肺中MicroRNA，U6和5S表达的血清MicroRNA谱以及癌症相关的变化。将在对照和癌症轴承动物中测量改性的组蛋白和RNA聚合酶II/III到U6、5s和精选的MicroRNA基因的调节区域的募集。血清将分析小鼠IL-6。 ii）前瞻性地研究血清U6，5s和选择miRNA水平在乳腺癌治疗过程中是否改变。乳腺癌患者的血清在开始新辅助疗法之前，完成治疗后，手术前立即进行手术后，将检查u6、5S RNA和选择microRNA的血清。如果癌症是血清中上述microRNA/小RNA的主要来源，则在新辅助治疗和/或手术后，它们的水平应下降。如果特定的microRNA是宿主衍生的，并且其在远处器官中的表达变化是永久性的，则治疗不应影响其表达。长期目标是确定癌症引起的其他器官的附带损害，以及这种损害如何影响癌症患者的整体健康状况。 公共卫生相关性：该提案将检查乳腺癌患者血清中检测到的microRNA和小RNA是否起源于癌症或远处的器官。癌症患者的慢性炎症状况可能会导致肝脏和肺部永久基因表达的变化，从而导致血清microRNA和小RNA水平改变。循环的microRNA可能是无形的癌症的长臂，因为循环的microRNA可以与异型细胞融合并影响基因表达。

项目成果

Cancer affects microRNA expression, release, and function in cardiac and skeletal muscle.

• DOI: 10.1158/0008-5472.can-13-2817
• 发表时间: 2014-08-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Chen D;Goswami CP;Burnett RM;Anjanappa M;Bhat-Nakshatri P;Muller W;Nakshatri H
• 通讯作者: Nakshatri H