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. 2019 Aug;20(2):903-914.
doi: 10.3892/mmr.2019.10314. Epub 2019 May 30.

Identification of key candidate genes involved in melanoma metastasis

Jia Chen  1 , Fei Wu  1 , Yu Shi  2 , Degang Yang  3 , Mingyuan Xu  1 , Yongxian Lai  4 , Yeqiang Liu  1
Affiliations

Identification of key candidate genes involved in melanoma metastasis

Jia Chen et al. Mol Med Rep. 2019 Aug.

Abstract

Metastasis is the most lethal stage of cancer progression. The present study aimed to investigate the underlying molecular mechanisms of melanoma metastasis using bioinformatics. Using the microarray dataset GSE8401 from the Gene Expression Omnibus database, which included 52 biopsy specimens from patients with melanoma metastasis and 31 biopsy specimens from patients with primary melanoma, differentially expressed genes (DEGs) were identified, subsequent to data preprocessing with the affy package, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A protein‑protein interaction (PPI) network was constructed. Mutated genes were analyzed with 80 mutated cases with melanoma from The Cancer Genome Atlas. The overall survival of key candidate DEGs, which were within a filtering of degree >30 criteria in the PPI network and involved three or more KEGG signaling pathways, and genes with a high mutation frequency were delineated. The expression analysis of key candidate DEGs, mutant genes and their associated genes were performed on UALCAN. Of the 1,187 DEGs obtained, 505 were upregulated and 682 were downregulated. 'Extracellular exosome' processes, the 'amoebiasis' pathway, the 'ECM‑receptor interaction' pathway and the 'focal adhesion' signaling pathway were significantly enriched and identified as important processes or signaling pathways. The overall survival analysis of phosphoinositide‑3‑kinase regulator subunit 3 (PIK3R3), centromere protein M (CENPM), aurora kinase A (AURKA), laminin subunit α 1 (LAMA1), proliferating cell nuclear antigen (PCNA), adenylate cyclase 1 (ADCY1), BUB1 mitotic checkpoint serine/threonine kinase (BUB1), NDC80 kinetochore complex component (NDC80) and protein kinase C α (PRKCA) in DEGs was statistically significant. Mutation gene analysis identified that BRCA1‑associated protein 1 (BAP1) had a higher mutation frequency and survival analysis, and its associated genes in the BAP1‑associated PPI network, including ASXL transcriptional regulator 1 (ASXL1), proteasome 26S subunit, non‑ATPase 3 (PSMD3), proteasome 26S subunit, non ATPase 11 (PSMD11) and ubiquitin C (UBC), were statistically significantly associated with the overall survival of patients with melanoma. The expression levels of PRKCA, BUB1, BAP1 and ASXL1 were significantly different between primary melanoma and metastatic melanoma. Based on the present study, 'extracellular exosome' processes, 'amoebiasis' pathways, 'ECM‑receptor interaction' pathways and 'focal adhesion' signaling pathways may be important in the formation of metastases from melanoma. The involved genes, including PIK3R3, CENPM, AURKA, LAMA1, PCNA, ADCY1, BUB1, NDC80 and PRKCA, and mutation associated genes, including BAP1, ASXL1, PSMD3, PSMD11 and UBC, may serve important roles in metastases of melanoma.

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Figures

Figure 1.
Figure 1.
Data normalization and identification of differentially expressed genes in GSE8401. (A) Boxplot for normalized gene expression data and (B) volcano plot of significantly differentially expressed genes. UP, upregulated; DW, downregulated; NoDiff, no difference.
Figure 2.
Figure 2.
Gene Ontology and signaling pathway enrichment analysis. (A) Gene Ontology and (B) signaling pathway enrichment analysis of differentially expressed genes. MF, molecular function; CC, cellular component; BP, biological process.
Figure 2.
Figure 2.
Gene Ontology and signaling pathway enrichment analysis. (A) Gene Ontology and (B) signaling pathway enrichment analysis of differentially expressed genes. MF, molecular function; CC, cellular component; BP, biological process.
Figure 3.
Figure 3.
Differentially expressed gene protein-protein interaction network. Red nodes represent upregulated genes and blue nodes represent downregulated genes. The more the degree of the node, the bigger the nodes.
Figure 4.
Figure 4.
Differentially expressed gene Kyoto Encyclopedia of Genes and Genomes network analysis. The larger size of the nodes represent larger enrichment scores and different colors represent the different enrichment modules.
Figure 5.
Figure 5.
Overall survival curves of key candidate genes in the protein-protein network. Overall survival curves of (A) CENPM, (B) BUB1, (C) AURKA, (D) ADCY1, (E) PRKCA, (F) PIK3R3, (G) PCNA, (H) NDC80 and (I) LAMA1. CENPM, centromere protein M; BUB1, BUB1 mitotic checkpoint serine/threonine kinase; AURKA, aurora kinase A; ADCY1, adenylate cyclase 1; PRKCA, protein kinase C α; PIK3R3, phosphoinositide-3-kinase regulator subunit 3; PCNA, proliferating nuclear antigen; NDC80, NDC80 kinetochore complex component; LAMA1, laminin subunit α 1; TPM, transcripts per million.
Figure 6.
Figure 6.
Top 50 mutated genes in 80 mutated cases with melanoma.
Figure 7.
Figure 7.
BAP1-associated gene PPI network. Red nodes represent upregulated genes and blue nodes represent downregulated genes. The larger size of the nodes represent more degrees in the global PPI network and lines indicate interactions. BAP1, BRCA1 associated protein 1; PPI, protein-protein interaction.
Figure 8.
Figure 8.
Overall survival curves of BAP1 and its associated genes. Overall survival curves of (A) BAP1, (B) PSMD3, (C) PSMD11, (D) UBC and (E) ASXL1. BAP1, BRCA1 associated protein 1; PSMD3, proteasome 26S subunit, non-ATPase 3; PSMD11, proteasome 26S subunit, non ATPase 11; UBC, ubiquitin C; ASXL1, ASXL transcriptional regulator 1; TPM, transcripts per million; HR, hazard ratio.
Figure 9.
Figure 9.
Overall survival curves of associated protein 1 in tumor cases with metastasis.
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