Role of microRNAs in malignant progression

我的长期目标是了解microRNA在调节肿瘤转移中的作用和机制， 并为恶性疾病开发新的候选疗法。越来越明显的是， 癌症发病机制可能涉及一个称为microRNA的小非编码RNA超家族。而 许多microRNA的致癌或肿瘤抑制功能已经被表征， microRNA在介导转移中所起的作用，直到最近才由我和几个 其他各组在我最初的筛选中，我确定了三种microRNA，它们在哺乳动物中表达最显著。 人乳腺癌细胞系：mIR-155、miR-9和miR-10 b。后续功能实验 证明miR-10 b的过表达可诱导两种肿瘤的侵袭和远处转移。 乳腺癌的原位模型。在这个奖项的K99阶段，我发现，治疗沉默 miR-10 b与“miR-10 b抑制小鼠乳腺肿瘤模型中的转移。另外我 将miR-9鉴定为抑制E-钙粘蛋白和促进转移的microRNA。在R 00阶段，我将 通过使用分子、遗传、药理学和基因组方法扩展这些先前的研究。 具体而言，我将通过使用多个模型和测试组合来进行ECOOMLR-10 b研究 在小鼠中;我将建立一个基因工程小鼠模型，以确定作用， miR-10 b在自发性乳腺癌正常发育和转移进展中的作用机制 癌症;我将探索miR-10 b在转移形成中的细胞非自主效应。同时，我 我将对miR-9进行临床前研究;我还将研究E-cadherin非依赖性 miR-9在肿瘤细胞中的作用总之，这些研究将能够更准确地评估 这些microRNA在恶性进展中的作用和机制，这将使我能够启动我的 独立研究计划，并获得R 01应用的初步数据。

My long-term goal is to understand the role and mechanisms of microRNAs in regulating tumor metastasis, and to develop new candidate therapies for malignant diseases. It has become increasingly evident that cancer pathogenesis can Involve a superfamily of small non-coding RNAs named microRNAs. While the oncogenic or tumor-suppressing functions of a number of microRNAs have been characterized, the role played by microRNAs in mediating metastasis was addressed only recently by work from myself and several other groups. In my initial screening, I identified three microRNAs that are most significantly upregulated in human breast cancer cell lines: mlR-155, miR-9, and miR-10b. Subsequent funcitonal experiments demonstrated that overexpression of miR-10b induced tumor invasion and distant metastasis in two orthotopic models of breast cancer. In the K99 phase of this award, I discovered that therapeutic silencing of miR-10b with 'antagomirs' suppressed metastasis in a mouse mammary tumor model. In addition, I identified miR-9 as an E-cadherin-suppressing and metastasis-promoting microRNA. In the R00 phase, I will extend these previous-studies by using molecular, genetic, pharmacological, and genomic approaches. Specifically, I will pursue the antagomlr-10b study by using multiple models and testing combination therapies In mice; I will establish a genetically engineered mouse model to determine the role and mechanisms of miR-10b In normal development and In metastatic progression of spontaneous breast cancer; and I will explore the cell non-autonomous effects of miR-10b In metastasis formation. In parallel, I will perform pre-clinical studies with the miR-9 antagomir; and I will also investigate E-cadherin-independent functions of miR-9 in tumor cells. Taken together, these studies will enable more precise evaluation of the role and mechanisms of these microRNAs In malignant progression, and will allow me to launch my independent research program and obtain preliminary data for R01 application.