Gong Xue, Zhao Hongjuan, Saar Matthias, Peehl Donna M, Brooks James D
Department of Urology, School of Medicine, Stanford University, Stanford, California, USA.
Department of Pathology, School of Medicine, Stanford University, Stanford, California, USA.
Kidney Cancer. 2019 Aug 7;3(2):119-132. doi: 10.3233/KCA-190051.
Clear cell renal cell carcinoma (ccRCC) is molecularly diverse and distinct molecular subtypes show different clinical outcomes. MicroRNAs (miRNAs) are essential components of gene regulatory networks and play a crucial role in progression of many cancer types including ccRCC.
Identify prognostic miRNAs and determine the role of miR-22 in ccRCC.
Hierarchical clustering was done in R using gene expression profiles of over 450 ccRCC cases in The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis was performed to identify prognostic miRNAs in the TCGA dataset. RNA-Seq was performed to identify miR-22 target genes in primary ccRCC cells and Matrigel invasion assay was performed to assess the effects of miR-22 overexpression on cell invasion.
Hierarchical clustering analysis using 2,621 prognostic genes previously identified by our group demonstrated that ccRCC patients with longer overall survival expressed lower levels of genes promoting proliferation or immune responses, while better maintaining gene expression associated with cortical differentiation and cell adhesion. Targets of 26 miRNAs were significantly enriched in the 2,621 prognostic genes and these miRNAs were prognostic by themselves. MiR-22 was associated with poor overall survival in the TCGA dataset. Overexpression of miR-22 promoted invasion of primary ccRCC cells and modulated transcriptional programs implicated in cancer progression including DNA repair, cell proliferation and invasion.
Our results suggest that ccRCCs with differential clinical outcomes have distinct transcriptomes for which miRNAs could serve as master regulators. MiR-22, as a master regulator, promotes ccRCC progression at least in part by enhancing cell invasion.
透明细胞肾细胞癌（ccRCC）在分子层面具有多样性，不同的分子亚型显示出不同的临床结局。微小RNA（miRNA）是基因调控网络的重要组成部分，在包括ccRCC在内的多种癌症类型的进展中发挥关键作用。
鉴定预后相关的miRNA，并确定miR-22在ccRCC中的作用。
使用R语言对癌症基因组图谱（TCGA）中450多例ccRCC病例的基因表达谱进行层次聚类。进行Kaplan-Meier分析以鉴定TCGA数据集中的预后相关miRNA。进行RNA测序以鉴定原发性ccRCC细胞中的miR-22靶基因，并进行基质胶侵袭试验以评估miR-22过表达对细胞侵袭的影响。
使用我们小组先前鉴定的2621个预后相关基因进行的层次聚类分析表明，总生存期较长的ccRCC患者表达促进增殖或免疫反应的基因水平较低，同时更好地维持与皮质分化和细胞黏附相关的基因表达。26个miRNA的靶基因在2621个预后相关基因中显著富集，并且这些miRNA自身也具有预后意义。在TCGA数据集中，miR-22与较差的总生存期相关。miR-22过表达促进原发性ccRCC细胞的侵袭，并调节与癌症进展相关的转录程序，包括DNA修复、细胞增殖和侵袭。
我们的结果表明，具有不同临床结局的ccRCC具有不同的转录组，miRNA可作为其主要调节因子。作为主要调节因子，miR-22至少部分通过增强细胞侵袭促进ccRCC进展。
