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上皮-间充质转化相关 microRNA/mRNA 特征与透明细胞肾细胞癌的转移和预后相关。

Epithelial-mesenchymal transition-associated microRNA/mRNA signature is linked to metastasis and prognosis in clear-cell renal cell carcinoma.

机构信息

Masaryk University, Central European Institute of Technology (CEITEC), Kamenice 5, 625 00, Brno, Czech Republic.

Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Zluty kopec 7, 656 53, Brno, Czech Republic.

出版信息

Sci Rep. 2016 Aug 23;6:31852. doi: 10.1038/srep31852.

Abstract

Clear-cell renal cell carcinomas (ccRCCs) are genetically heterogeneous tumors presenting diverse clinical courses. Epithelial-mesenchymal transition (EMT) is a crucial process involved in initiation of metastatic cascade. The aim of our study was to identify an integrated miRNA/mRNA signature associated with metastasis and prognosis in ccRCC through targeted approach based on analysis of miRNAs/mRNAs associated with EMT. A cohort of 230 ccRCC was included in our study and further divided into discovery, training and validation cohorts. EMT markers were evaluated in ccRCC tumor samples, which were grouped accordingly to EMT status. By use of large-scale miRNA/mRNA expression profiling, we identified miRNA/mRNA with significantly different expression in EMT-positive tumors and selected 41 miRNAs/mRNAs for training phase of the study to evaluate their diagnostic and prognostic potential. Fifteen miRNAs/mRNAs were analyzed in the validation phase, where all evaluated miRNA/mRNA candidates were confirmed to be significantly deregulated in tumor tissue. Some of them significantly differed in metastatic tumors, correlated with clinical stage, with Fuhrman grade and with overall survival. Further, we established an EMT-based stage-independent prognostic scoring system enabling identification of ccRCC patients at high-risk of cancer-related death. Finally, we confirmed involvement of miR-429 in EMT regulation in RCC cells in vitro.

摘要

透明细胞肾细胞癌(ccRCCs)是遗传异质性肿瘤,表现出不同的临床过程。上皮-间充质转化(EMT)是启动转移级联反应的关键过程。我们的研究目的是通过基于 EMT 相关 miRNA/mRNA 分析的靶向方法,确定与 ccRCC 转移和预后相关的整合 miRNA/mRNA 特征。我们的研究纳入了 230 例 ccRCC 患者,并进一步分为发现、训练和验证队列。评估了 ccRCC 肿瘤样本中的 EMT 标志物,并根据 EMT 状态对其进行分组。通过大规模 miRNA/mRNA 表达谱分析,我们确定了 EMT 阳性肿瘤中表达差异显著的 miRNA/mRNA,并选择了 41 个 miRNA/mRNA 用于研究的训练阶段,以评估其诊断和预后潜力。在验证阶段分析了 15 个 miRNA/mRNA,所有评估的 miRNA/mRNA 候选物在肿瘤组织中均被证实存在显著失调。其中一些在转移性肿瘤中存在显著差异,与临床分期、Fuhrman 分级和总生存期相关。此外,我们建立了基于 EMT 的与分期无关的预后评分系统,能够识别出癌症相关死亡风险高的 ccRCC 患者。最后,我们在体外证实了 miR-429 在 RCC 细胞 EMT 调控中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c20/4994011/b866253d1dd8/srep31852-f1.jpg

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