Role of microRNAs in malignant progression

我的长期目标是了解microRNAs在调节肿瘤转移中的作用和机制， 并开发治疗恶性疾病的新候选疗法。越来越明显的是， 癌症的发病机制可能涉及一个名为microRNAs的非编码小RNA超家族。而当 一些microRNAs的致癌或抑瘤功能已经被表征，其作用 MicroRNAs在介导肿瘤转移中所起的作用直到最近我和几个人的工作才得到解决 其他团体。在我最初的筛查中，我发现了三个最显著上调的microRNAs 人乳腺癌细胞系：MLR-155、miR-9和miR-10b。随后的功能实验 证实了miR-10b的过表达诱导了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，我发现治疗性沉默 含有“对抗剂”的MIR-10b抑制了小鼠乳腺肿瘤模型的转移。此外，我 鉴定miR-9是一种抑制E-钙粘附素和促进转移的microRNA。在R00阶段，我将 通过使用分子、遗传学、药理学和基因组学方法扩展这些先前的研究。 具体地说，我将通过使用多个模型和测试组合来进行antagomlr-10b研究 对小鼠的治疗；我将建立一个基因工程小鼠模型，以确定 MiR-10b在自发性乳腺正常发育和转移进展中的作用机制 我将探索miR-10b在转移形成中的细胞非自主作用。同时，我 我将对miR-9 Anagomir进行临床前研究；我还将研究E-钙粘附素非依赖性 MiR-9在肿瘤细胞中的功能。综上所述，这些研究将使我们能够更准确地评估 这些microRNA在恶性进展中的作用和机制，并将使我能够启动我的 独立研究计划，并获得R01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.