Rao Srinivasa R, Howarth Alison, Kratschmer Patrick, Snaith Ann E, Yapp Clarence, Ebner Daniel, Hamdy Freddie C, Edwards Claire M
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.
Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, United Kingdom.
Front Oncol. 2020 Mar 13;10:292. doi: 10.3389/fonc.2020.00292. eCollection 2020.
Identifying new mechanisms that underlie the complex process of metastasis is vital to combat this fatal step in prostate cancer (PCa) progression. Small non-coding RNAs are emerging as important regulators of tumor cell biology. Here we take an integrative approach to elucidate the contribution of microRNAs to metastatic progression, combining transcriptomic analysis with functional screens for migration and morphology. We developed high-content microscopy, high-throughput functional screens for migration and morphology in PCa cells using a microRNA library. RNA-Seq analysis of paired epithelial and mesenchymal PCa cells identified differential expression of 200 microRNAs. Data integration identified two microRNAs that inhibited migration, induced an epithelial-like morphology and were increased in epithelial PCa cells. An overrepresentation of the AAGUGC seed sequence was detected in all three datasets. Analysis of published datasets of patients with PCa identified microRNAs of clinical relevance. The integration of high-throughput functional and expression analyses identifies microRNAs with clinical significance that modulate metastatic behavior in PCa.
识别构成转移复杂过程基础的新机制对于对抗前列腺癌（PCa）进展中的这一致命步骤至关重要。小非编码RNA正成为肿瘤细胞生物学的重要调节因子。在这里，我们采用综合方法来阐明微小RNA对转移进展的贡献，将转录组分析与迁移和形态功能筛选相结合。我们使用微小RNA文库开发了用于PCa细胞迁移和形态的高内涵显微镜、高通量功能筛选。对配对的上皮和间充质PCa细胞进行RNA测序分析，确定了200种微小RNA的差异表达。数据整合确定了两种抑制迁移、诱导上皮样形态且在上皮PCa细胞中增加的微小RNA。在所有三个数据集中均检测到AAGUGC种子序列的过度富集。对已发表的PCa患者数据集的分析确定了具有临床相关性的微小RNA。高通量功能和表达分析的整合确定了对PCa转移行为有调节作用且具有临床意义的微小RNA。
