New mechanistic insights of clear cell renal cell carcinoma from integrated miRNA and mRNA expression profiling studies
New mechanistic insights of clear cell renal cell carcinoma from integrated miRNA and mRNA expression profiling studies
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整合 miRNA 和 mRNA 表达谱研究对透明细胞肾细胞癌的新机制认识
DOI：
10.1016/j.biopha.2018.12.099
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发表时间：
2019-03-01
影响因子：
7.5
通讯作者：
Zheng, Junfang
中科院分区：
文献类型：
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作者：
Qi, Yijun;Wang, Lei;Zheng, Junfang
据报道，来自混合样本的透明细胞肾细胞癌 (ccRCC) 组织中的差异表达 (DE) microRNA (miRNA) 会影响 ccRCC 的肿瘤发生和进展。然而，缺乏对参与疾病所有四个阶段的各种途径的 miRNA-mRNA 调控网络的系统研究。在本研究中，我们应用微阵列技术对ccRCC不同阶段患者的ccRCC组织中的miRNome和转录组进行了整合分析。通过与相应的邻近正常组织进行比较，总共鉴定出 604 个 DEmiRNA 和 6892 个 DE 基因（DEG）。使用经过验证的 mirWalk 模块搜索 miRNA 与 DEG 的配对，并通过与我们研究中的 DEmiRNA 进行比较来确认配对。我们的结果表明，ccRCC 的不同阶段具有不同的 miRNA/mRNA 谱。然而，在 ccRCC 的各个阶段，DEmiRNA 的靶标丰富了四种常见途径（补体和凝血级联、细胞色素 P450 的异生物质代谢途径、PPAR 信号传导途径和醛固酮调节的钠重吸收途径）。我们对目标基因最多的 miR-16 的数据进行了广泛的分析，发现其差异表达在癌症基因组图谱数据集中得到了验证。我们还通过基因集富集分析和体外实验验证了miR-16表达与靶通路之间的相关性。高 miR-16 水平也与 ccRCC 较短的生存时间相关。我们的工作对 ccRCC 不同阶段的 miRNA、mRNA 和 miRNA 调控的通路进行了系统分析。我们的跨组学结果还确定了在疾病的所有阶段中功能异常的四种常见途径。这些途径可能对 ccRCC 的发生和进展至关重要。这些常见的功能失调途径有可能作为治疗靶点和诊断生物标志物，而仅在 I 期组织和血液中差异表达的 miRNA (miR-20, 484, 497) 可用于诊断早期 ccRCC 患者。
Differentially expressed (DE) microRNAs (miRNAs) in clear cell renal cell carcinoma (ccRCC) tissues from pooled samples were reported to affect the tumorigenesis and progression of ccRCC. However, systematic studies on the miRNA-mRNA regulatory networks involved in various pathways in all four stages of the disease are lacking. In this study, we applied microarray technology to perform an integrated analysis of the miRNome and transcriptome in ccRCC tissues from patients at different stages of ccRCC. A total of 604 DEmiRNAs and 6892 DEgenes (DEGs) were identified by comparison with corresponding adjacent normal tissues. The pairing of miRNAs with DEGs were searched using validated miRWalk module, and the pairs were confirmed by comparing with DEmiRNAs in our study. Our results demonstrated that different stages of ccRCC had distinct miRNA/ mRNA profiles. However, four common pathways (the complement and coagulation cascades, the pathway for the metabolism of xenobiotics by cytochrome P450, the PPAR signaling pathway, and the pathway for aldosterone-regulated sodium reabsorption) were enriched by targets of DEmiRNAs at all stages of ccRCC. We carried out an extensive analysis of data on miR-16, which had the most target genes, and found that its differential expression was validated in The Cancer Genome Atlas dataset. We also verified the correlation between miR-16 expression and target pathways by gene set enrichment analysis and in vitro experiments. High miR-16 level was also associated with shorter survival time in ccRCC. Our work presents a systematic profiling of miRNA, mRNA and pathways regulated by miRNAs in different stages of ccRCC. Our cross-omics results also identify four common pathways that function aberrantly in all stages of the disease. These pathways are likely to be critical in occurrence and progression of ccRCC. These common dysfunctional pathways have the potential to serve as therapeutic targets and diagnostic biomarkers, whereas miRNAs (miR-20, 484, 497) differentially expressed in only stage I tissues and in blood could be used to diagnose early-stage ccRCC patients.