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. 2021 Jan 19:10:593601.
doi: 10.3389/fonc.2020.593601. eCollection 2020.

A Novel mRNA-miRNA Regulatory Sub-Network Associated With Prognosis of Metastatic Clear Cell Renal Cell Carcinoma

Tianyu Yang  1 , Xiaofen Miao  2 , Zhanxiang Bai  3 , Jian Tu  1 , Shanshan Shen  1 , Hui Niu  1 , Wei Xia  1 , Juan Wang  4 , Yongsheng Zhang  1
Affiliations

A Novel mRNA-miRNA Regulatory Sub-Network Associated With Prognosis of Metastatic Clear Cell Renal Cell Carcinoma

Tianyu Yang et al. Front Oncol. .

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is a urinary disease with high incidence. The high incidence of metastasis is the leading cause of death in patients with ccRCC. This study was aimed to identify the gene signatures during the metastasis of ccRCC.

Methods: Two datasets, including one gene expression profile dataset and one microRNA (miRNA) expression profile dataset, were downloaded from Gene Expression Omnibus (GEO) database. The integrated bioinformatics analysis was performed using the (limma) R package, miRWalk, DAVID, STRING, Kaplan-Meier plotter databases. Quantitative real-time polymerase chain reaction (qPCR) was conducted to validate the expression of differentially expressed genes (DEGs) and DE-miRNAs.

Results: In total, 84 DEGs (68 up-regulated and 16 down-regulated) and 41 DE-miRNAs (24 up-regulated and 17 down-regulated) were screened from GSE22541 and GSE37989 datasets, respectively. Furthermore, 11 hub genes and 3 key miRNAs were identified from the PPI network, including FBLN1, THBS2, SCGB1A1, NKX2-1, COL11A1, DCN, LUM, COL1A1, COL6A3, SFTPC, SFTPB, miR-328, miR-502, and miR-504. The qPCR data showed that most of the selected genes and miRNAs were consistent with that in our integrated analysis. A novel mRNA-miRNA network, SFTPB-miR-328-miR-502-miR-504-NKX2-1 was found in metastatic ccRCC after the combination of data from expression, survival analysis, and experiment validation.

Conclusion: In conclusion, key candidate genes and miRNAs were identified and a novel mRNA-miRNA network was constructed in ccRCC metastasis using integrated bioinformatics analysis and qPCR validation, which might be utilized as diagnostic biomarkers and molecular targets of metastatic ccRCC.

Keywords: bioinformatics analysis; cancer metastasis; clear cell renal cell carcinoma; hub genes; miRNAs.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Differentially expressed genes and miRNAs in metastatic ccRCC and primary ccRCC tissues. (A) Volcano plot of differentially expressed mRNAs from GSE22541 dataset; (B) Volcano plot of differentially expressed miRNAs from GSE37989 dataset; (C) Heatmap of differentially expressed mRNAs from GSE22541 dataset; (D) Heatmap of differentially expressed miRNAs from GSE37989 dataset.
Figure 2
Figure 2
Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) enrichment analysis for functions of differentially expressed genes in metastatic ccRCC. (A) The top 20 most significant KEGG pathway terms; (B) The top 10 most significant changes in the GO biological process; (C) The top 10 most significant changes in the GO cellular component; (D) The top 10 most significant changes in the GO molecular function.
Figure 3
Figure 3
Protein-protein interaction (PPI) network. mRNAs and miRNAs are indicated as ellipsoid and diamond, respectively. The gray dotted line represents the interaction of the miRNA-mRNAs. The green line represents the interaction of the proteins. The yellow indicates high expression, and blue indicates low expression.
Figure 4
Figure 4
PPI network of hub genes and key miRNAs. mRNAs and miRNAs are indicated as ellipsoid and diamond, respectively. The gray dotted line represents the interaction of the miRNA-mRNAs. The green line represents the interaction of the proteins. The yellow indicates high expression, and blue indicates low expression. * indicates hsa-miR-452-3p.
Figure 5
Figure 5
Kaplan-Meier survival analysis for the correlation of 11 hub genes with overall survival of the patients with ccRCC. The vertical coordinate represents the survival probability of ccRCC patients. The red curve represents ccRCC patients with up-regulation of genes, while the black curve represents ccRCC patients with down-regulation of genes.
Figure 6
Figure 6
Kaplan-Meier survival analysis for the correlation of seven down-regulated key miRNAs with overall survival of the patients with ccRCC. The vertical coordinate represents the survival probability of ccRCC patients. The red curve represents ccRCC patients with up-regulation of miRNAs, while the black curve represents ccRCC patients with down-regulation of miRNAs. * indicates hsa-miR-452-3p.
Figure 7
Figure 7
The qPCR results of 11 hub genes and 3 key miRNAs in 20 ccRCC tissues and paired adjacent normal kidney tissues. The vertical coordinate represents the expression levels of genes and miRNAs. Ctrl: Paracancer tissues. * indicates P<0.05; ** indicates P<0.01.
Figure 8
Figure 8
The novel mRNA-miRNA regulatory network associated with prognosis of the patients with ccRCC.
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