Identifying a network of microRNAs and genes that regulate breast tumor metastasis

识别调节乳腺肿瘤转移的 microRNA 和基因网络

• 批准号: 9459147
• 负责人: Huiping Liu
• 金额: $ 19.73万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9459147
• 关键词: Identifying; network; microRNAs; genes; regulate

Proposal: Identifying a network of miRNAs and genes that regulate breast tumor metastasis Abstract Metastasis is the major cause of death in breast cancer patients. However, the molecular mechanisms underlying tumor initiation and metastasis are not clear. We have recently identified tumor initiation cells (TICs) from human breast tumors 1,2. TICs carry certain properties of stem cells, are more resistant to conventional cancer therapies, and are involved in tumor metastasis. How to effectively target TICs or metastasis initiating cells (MICs) thus becomes one of the most propelling questions. Endogenous single strand small RNAs of 20- 22 nucleotides in length, known as microRNAs (miRNAs, miRs), have emerged to be powerful regulators of tumor progression 3-15. In this project, we aim to characterize novel miRs that regulate human breast cancer initiation and metastasis and identify their target genes. Then in our future endeavors, we will examine miR regulation mechanisms at the transcriptional level and further translate our understanding to clinical applications, such as novel cancer biomarkers or therapeutics. Most previous metastasis models are limited in their ability to fully represent human tumors, due to genetic changes accumulated in culture for human cancer cell lines, genetic differences in mouse tumor models compared to human tumors, and bypassing the natural steps of metastasis via bloodstream inoculations. This project will take advantage of our recently established human-in-mouse breast cancer models, which are derived from clinical tumor specimens and develop spontaneous lung or lymph node metastases upon orthotopic transplantation into mouse mammary fat pads. To closely monitor breast tumor initiation and metastasis in vivo, we have also transduced primary cancer cells with optical reporters and improved the detection sensitivity to 10 cells in vivo via non-invasive bioluminescence imaging. MiRs are more stable and resistant to analysis protocols than mRNAs, thus serving as promising novel cancer biomarkers. Furthermore, they are endogenous small RNAs with little toxicity compared to compound drugs; therefore hold the promise to be developed as innovative cancer therapeutics. Our long-term goal is to combine our understanding of tumor initiation and metastasis with knowledge in multi- disciplinary technology (such as chemistry and bioengineering) to improve clinical medicine and reduce cancer mortality. Transcription Factors In vivo Tumor initiation metastasis Future 1 Novel miRNAs 1 Future 2 In vitro Tumor growth Cell invasion Target Differentiation Genes Drug-resistance Preclinical Biomarkers Therapeutics 2 A schematic figure of aims: (1) to characterize and validate miRNA candidate functions, (2) to identify miRNA targets and their importance in BTICs and metastasis, (Future 1) transcriptional regulation of miRNAs by transcriptional factors, and (Future 2) preclinical studies of miRNAs and genes serving as novel biomarkers and/or therapeutic targets for breast cancer.

提案：确定调节乳腺肿瘤转移的miRNA和基因网络 抽象的 转移是乳腺癌患者死亡的主要原因。但是，分子机制 潜在的肿瘤起始和转移尚不清楚。我们最近确定了肿瘤起始细胞（TICS） 来自人类乳腺肿瘤1,2。抽动具有某些干细胞的特性，对常规的耐药性更具耐药性 癌症疗法，并参与肿瘤转移。如何有效靶向抽动或转移 因此，细胞（MIC）成为最具推动性的问题之一。 20-的内源性单链小rNA 22个长度的核苷酸，称为microRNA（miRNA，mirs），已成为强大的调节剂 肿瘤进展3-15。在这个项目中，我们旨在表征调节人类乳腺癌的新型miRS 启动和转移并确定其靶基因。然后在我们未来的努力中，我们将检查Mir 转录水平的调节机制，并进一步将我们的理解转化为临床 应用，例如新型的癌症生物标志物或治疗剂。 由于遗传 人类癌细胞系中培养中积累的变化，小鼠肿瘤模型的遗传差异 与人类肿瘤相比，通过血液接种绕过转移的自然步骤。这 项目将利用我们最近建立的室内乳腺癌模型， 源自临床肿瘤标本，并在 原位移植到小鼠乳腺脂肪垫中。密切监测乳腺肿瘤的启动和 转移在体内，我们还用光学报道转导了原代癌细胞，并改善了原代癌细胞 通过非侵入性生物发光成像检测对10个细胞体内10个细胞的敏感性。 mirs更稳定， 比mRNA具有抗性分析方案，因此是有前途的新型癌症生物标志物。此外， 与复合药物相比，它们是内源性的小RNA，毒性很小。因此持有承诺 要作为创新的癌症治疗剂开发。 我们的长期目标是将我们对肿瘤起始和转移的理解与多种知识相结合 纪律技术（例如化学和生物工程），以改善临床医学并减少癌症 死亡。 转录 因素 体内 肿瘤的启动 转移 未来1 小说mirnas 1 未来2 体外 肿瘤生长 细胞入侵 目标差异 基因抗药性 临床前 生物标志物 疗法 2 目的的示意图：（1）表征和验证miRNA候选功能，（2） 确定miRNA靶标及其在BTIC和转移中的重要性，（未来1）转录 通过转录因子和（未来2）miRNA的miRNA调节miRNA 以及作为乳腺癌的新生物标志物和/或治疗靶标的基因。