The miR-183/182/96 cluster functions as a potential carcinogenic factor and prognostic factor in kidney renal clear cell carcinoma

Abstract

Kidney renal clear cell carcinoma (KIRC) is the most common type of renal cell carcinoma. While a number of treatments have been developed over the past few decades, the prognosis of patients with KIRC remains poor due to tumor metastasis and recurrence. Therefore, the molecular mechanisms of KIRC require to be elucidated in order to identify novel biomarkers. MicroRNAs (miRNAs/miRs) have been studied as important regulators of gene expression in a variety of cancer types. In the present study, a bioinformatics analysis of differentially expressed miRNAs in KIRC vs. normal tissues was performed based on raw miRNA expression data and patient information downloaded from the The Cancer Genome Atlas database. Furthermore, the clinical significance of differentially expressed miRNAs was evaluated, and their target genes and biological effects were further predicted. After applying the cut-off criteria of an absolute fold change of ≥2 and P<0.05, 127 differentially expressed miRNAs between KIRC and normal tissues were identified. The product of the miR-183/182/96 gene cluster, namely miR-183, miR-96 and miR-182, was revealed to be associated with multiple clinicopathological features of KIRC and to have a significant predictive and prognostic value. Subsequent functional enrichment analysis indicated that the target genes of the three miRNAs are associated with various Panther pathways, including the α-adrenergic receptor signaling pathway, metabotropic glutamate receptor group I pathway, histamine H1 receptor-mediated signaling pathway and thyrotropin-releasing hormone receptor signaling pathway. In addition, major enriched gene ontology terms in the category biological process included the intracellular signaling cascade, cellular macromolecule catabolic process and response to DNA damage stimulus. Taken together, the present study suggested that miR-183, miR-96 and miR-182 may function as potential carcinogenic factors in KIRC and may be utilized as prognostic predictors.

Keywords: bioinformatics; carcinogenic factor; kidney renal clear cell carcinoma; microRNA-183/182/96; prognostic factor.

Figure 1.

(A) miRNA expression profiles and identification of miR-183, miR-96 and miR-182 as differentially expressed between KIRC and normal tissues. Blue indicates normal tissues and orange represents KIRC tissues. (B) Volcano plot of differentially expressed miRNAs between KIRC and normal tissues. (C) The levels of miR-183, miR-96 and miR-182 were significantly decreased in KIRC cell lines (LoMet-ccRCC, 786-O) compared with the human renal tubular epithelial cell line HKC-5 as indicated by reverse transcription-quantitative polymerase chain reaction analysis. *P<0.05 vs. HKC. UP, upregulation; DW, downregulation; KIRC, kidney renal clear cell carcinoma; miRNA/miR, microRNA.

Figure 2.

(A) ROC curve of miR-183, miR-96 and miR-182 between KIRC and normal tissues. (B-D) Kaplan-Meier curves of KIRC patients stratified based on the expression of (B) miR-183, (C) miR-96 and (D) miR-182 in their cancer tissues (high or low). ROC, receiver operating characteristic; AUC, area under curve; miR, microRNA; KIRC, kidney renal clear cell carcinoma.

Figure 3.

(A-C) Venn diagrams of target genes of (A) miR-183, (B) miR-96 and (C) miR-182 determined using Targetscan and miRDB. (D) Gene ontology terms in the category biological process enriched by target genes of miR-183, miR-96 and miR-182 shared between Targetscan and miRDB. (E) Panther pathways of consensus target genes of miR-183, miR-96 and miR-182. PI, phosphoinositide; miR, microRNA; Gq alpha, G-Protein, Gq alpha Family; Go alpha, G-Protein, Gi-Go Subunits.