Purpose: The aim of this study was to generate a novel miRNA expression signature to effectively assess nodal metastasis, distant metastasis and predict prognosis for patients with kidney renal clear cell carcinoma (KIRC) and explore its potential mechanism of affecting the prognosis. Method: Using expression profiles downloaded from the Cancer Genome Atlas database, we identified multiple miRNAs with differential expression between KIRC and paired normal tissues. The diagnostic values of the differentially expressed miRNAs for nodal metastasis and distant metastasis were evaluated by Receiver Operating Characteristic (ROC) curve analysis. Then, we evaluated the impact of miRNAs on overall survival (OS) by univariate and multivariate COX regression analyzes. This analysis was ultimately used to construct a miRNA signature that effectively assessed nodal metastasis, distant metastasis and predicted prognosis. The functional enrichment analysis of the miRNAs included in the signatures was used to explore its potential molecular mechanism in KIRC. Results: Based on our cutoff criteria (P < 0.05 and |log2FC| > 1.0), we identified 104 differentially expressed microRNAs (miRNAs), including 43 that were up-regulated in KIRC tissues and 61 that were down-regulated. We found 12 miRNAs were potentially diagnostic biomarkers of nodal metastasis and distant metastasis by ROC curve analysis. Two miRNAs (miRNA-21 and miRNA-223) were significant miRNAs independently associated with OS based on Cox univariate and multivariate analysis. We generated a signature index based on expression of these two miRNAs, and the two-miRNA signature is promising as a biomarker for diagnosing nodal metastasis, distant metastasis and predicting 5-year survival rate of KIRC with areas under the curve (AUC)=0.738, 0.659 and 0.731, respectively. Patients were stratified into high-risk and low-risk groups, according to median of the signature prognosis indexes. Patients in the high-risk group had significantly shorter survival times than those in the low-risk group (P = 0.000). The functional enrichment analysis suggested that the target genes of two miRNAs may be involved in various pathways related to cancer, p53 signaling pathway, apoptosis, and MAPK signaling pathway. Conclusion: The two-miRNA signature could assess nodal metastasis, distant metastasis and predict survival of KIRC. As a promising prediction tool, the mechanism of the two miRNAs in KIRC deserves further study.

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