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. 2020 Jan 16;11(7):1712-1726.
doi: 10.7150/jca.38379. eCollection 2020.

The Identification of Key Gene Expression Signature and Biological Pathways in Metastatic Renal Cell Carcinoma

Lin Bao  1 , Ye Zhao  2 , ChenChen Liu  1 , Qi Cao  1 , Yu Huang  1 , Ke Chen  1 , Zhengshuai Song  3
Affiliations

The Identification of Key Gene Expression Signature and Biological Pathways in Metastatic Renal Cell Carcinoma

Lin Bao et al. J Cancer. .

Abstract

Purpose: To investigate the potential mechanisms contributing to metastasis of clear cell renal cell carcinoma (ccRCC), screen the hub genes, associated pathways of metastatic ccRCC and identify potential biomarkers. Methods: The ccRCC metastasis gene expression profile GSE47352 was employed to analyze the differentially expressed genes (DEGs). DAVID was performed to assess Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The protein-protein interaction (PPI) network and modules were constructed. The function pathway, prognostic and diagnostic analysis of these hub genes was picked out to estimate their potential effects on metastasis of ccRCC. Results: A total of 873 DEGs were identified (503 upregulated genes and 370 downregulated genes). Meanwhile, top 20 hub genes were displayed. GO analysis showed that the top 20 hub genes were enriched in regulation of phosphatidylinositol 3-kinase signaling, positive regulation of DNA replication, protein autophosphorylation, protein tyrosine kinase activity, etc. KEGG analysis indicated these hub genes were enriched in the Ras signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, Pathways in cancer, etc. The GO and KEGG enrichment analyses for the hub genes disclosed important biological features of metastatic ccRCC. PPI network showed the interaction of top 20 hub genes. Gene Set Enrichment Analysis (GSEA) revealed that some of the hub genes was associated with metastasis, epithelial mesenchymal transition (EMT), hypoxia cancer and adipogenesis of ccRCC. Some top hub genes were distinctive and new discoveries compared with that of the existing associated researches. Conclusions: Our analysis uncovered that changes in signal pathways such as Ras signaling pathway, PI3K-Akt signaling pathway, etc. may be the main signatures of metastatic ccRCC. We identified several candidate biomarkers related with overall survival (OS) and disease-free survival (DFS) of ccRCC patients. Accordingly, they might be novel therapeutic targets and used as potential biomarkers for diagnosis, prognosis of ccRCC.

Keywords: biomarker; clear cell renal cell carcinoma; diagnosis; metastasis; prognosis..

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Protein-protein interaction network of the top 20 hub genes and modular analysis. (a)The DEGs of GSE47352. (b) The heatmap of 20 hub genes. (c)The PPI network of the top 20 hub genes. (d) module 1 (e) module 2 (f) module 3 of DEGs from PPI network.
Figure 2
Figure 2
Gene Ontology enrichment analysis and KEGG pathways of top 20 hub genes (a) GO analysis of top 20 hub genes. (b) KEGG pathway of top 20 hub genes.
Figure 3
Figure 3
Hub genes have prognostic value of overall survival. (a) RIPK4 (b) CDC42, (c) PTPN11, (d) KITLG, (e) IGF1R, (f) FLT1, (g) AURKB, (h) GNA13, (i) DLG2, (j) ACTN2, (k) CD80. The overall survival information was based on GEPIA database, P < 0.05 was considered statistically different.
Figure 4
Figure 4
Hub genes have prognostic value of disease-free survival. (a) RIPK4, (b) CDC42, (c) PTPN11, (d) KITLG, (e) IGF1R, (f) SERPINE1, (g) AURKB, (h) GNA13, (i) DLG2, (j) ACTN2. The disease-free survival information was based on GEPIA database, P < 0.05 was considered statistically different.
Figure 5
Figure 5
Diagnostic value of the selected top hub genes.
Figure 6
Figure 6
Expression of the selected top hub genes based on TCGA database.
Figure 7
Figure 7
AURKB is overexpression in ccRCC, and is correlated with various clinicopathological parameters. The high mRNA expression of AURKB was correlated with various clinicopathological parameters: (a) T stage, (b) lymph node metastasis, (c) distant metastases, (d) G stage.
Figure 8
Figure 8
Gene set enrichment analysis (GSEA) of AURKB. 10 representative functional gene sets enriched in ccRCC with AURKB highly expressed were listed.
Figure 9
Figure 9
Expression and Biological function of AURKB. (a) The expression of AURKB in ccRCC tumor(T) and adjacent normal tissues(N), (b)AURKB knockdown in ACHN cell lines, (c) Transwell assay of AURKB in ACHN cell lines.
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