Identification of Core Genes and Pathways in Melanoma Metastasis via Bioinformatics Analysis

Abstract

Metastasis is the leading cause of melanoma-related mortality. Current therapies are rarely curative for metastatic melanoma, revealing the urgent need to identify more effective preventive and therapeutic targets. This study aimed to screen the core genes and molecular mechanisms related to melanoma metastasis. A gene expression profile, GSE8401, including 31 primary melanoma and 52 metastatic melanoma clinical samples, was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between melanoma metastases and primary melanoma were screened using GEO2R tool. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analyses of DEGs were performed using the Database for Annotation Visualization and Integrated Discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape with Molecular Complex Detection (MCODE) plug-in tools were utilized to detect the protein–protein interaction (PPI) network among DEGs. The top 10 genes with the highest degrees of the PPI network were defined as hub genes. In the results, 425 DEGs, including 60 upregulated genes and 365 downregulated genes, were identified. The upregulated genes were enriched in ECM–receptor interactions and the regulation of actin cytoskeleton, while 365 downregulated genes were enriched in amoebiasis, melanogenesis, and ECM–receptor interactions. The defined hub genes included CDK1, COL17A1, EGFR, DSG1, KRT14, FLG, CDH1, DSP, IVL, and KRT5. In addition, the mRNA and protein levels of the hub genes during melanoma metastasis were verified in the TCGA database and paired post- and premetastatic melanoma cells, respectively. Finally, KRT5-specific siRNAs were utilized to reduce the KRT5 expression in melanoma A375 cells. An MTT assay and a colony formation assay showed that KRT5 knockdown significantly promoted the proliferation of A375 cells. A Transwell assay further suggested that KRT5 knockdown significantly increased the cell migration and cell invasion of A375 cells. This bioinformatics study provided a deeper understanding of the molecular mechanisms of melanoma metastasis. The in vitro experiments showed that KRT5 played the inhibitory effects on melanoma metastasis. Therefore, KRT5 may serve important roles in melanoma metastasis.

Identification of biomarkers and prediction of upstream miRNAs in diabetic nephropathy

“…It is widely used in analyzing the functional similarity between genes and identifying biological functions and pathways related to diseases by high-throughput biological data analysis ( 10 ). The Kyoto Encyclopedia of Genes and Genomes (KEGG) is a public and comprehensive database for understanding the advanced functions of cells and organisms from genomics and other high-throughput data sets, integrating genomes, biological pathways, diseases, drugs and chemicals ( 11 , 12 ). In order to understand the function of Hub genes, we used the DAVID database for GO functional analysis and KEGG pathway enrichment.…”

Role of extracellular matrix architecture and signaling in melanoma therapeutic resistance

“…Furthermore, the interaction of cancer cells with aligned ECM fibers promoted directional migration of cancer cells (102,114). In this regard, melanoma cells were found to mimic the directional migration of fibroblasts along collagen fibrils in a 3D collagen ECM model (114,115). Melanoma cells were described to elongate and migrate in parallel to collagen fibrils by extending actin-rich protrusions, called filapodia, which adhere to and detach from collagen fibrils in cycles, as the melanoma cells are migrating (115).…”

“…In this regard, melanoma cells were found to mimic the directional migration of fibroblasts along collagen fibrils in a 3D collagen ECM model (114,115). Melanoma cells were described to elongate and migrate in parallel to collagen fibrils by extending actin-rich protrusions, called filapodia, which adhere to and detach from collagen fibrils in cycles, as the melanoma cells are migrating (115). Furthermore, fibronectin was found to be an essential ECM adhesive component required for the directional migration of pancreatic, prostate and head and neck squamous carcinoma cells (116).…”

A Novel multi‐fruit acids formula design on molecular basis for skin brightening via a system biology approach

“…Each stage may involve the transduction of external signals, regulation of melanin synthesis limiting enzymes, and initiation of melanin signaling cascade. Meanwhile, it has been reported that the initiation, synthesis, and transport of melanin could be engaged in a variety of cells, 14 targets and pathways 15 with sophisticated cross‐influences 16 . However, previous attempts are usually confined to simple combinations on target genes or pathways, lacking a comprehensive understanding towards systematic network of pigmentation.…”