Identification of Potential Genes Associated with Vemurafenib Efficacy and Melanoma Prognosis
Objective: This work aimed to investigate the molecular mechanisms underlying the efficacy of vemurafenib as a treatment for melanoma.
Methods: The GSE52882 dataset, which includes A375 and A2058 melanoma cell lines treated with vemurafenib and dimethyl sulfoxide (DMSO), and clinical information associated with melanoma patients, were acquired from the Gene Expression Omnibus (GEO) database and University of California Santa Cruz (UCSC), respectively. Functional enrichment analysis, protein-protein interaction (PPI) network construction, sub-module analysis, and transcriptional regulation analysis were performed on overlapping differentially expressed genes (DEGs) identified in both cell lines. Finally, we performed a survival analysis based on the genes identified.
Results: A total of 447 consistently overlapping DEGs (176 up- and 271 down-regulated DEGs) were screened. Upregulated genes were enriched in pathways of neurotrophin signaling, estrogen signaling, and transcriptional misregulation in cancer. Downregulated DEGs played essential roles in melanogenesis, pathways of cancer, PI3K-Akt signaling pathway, and AMPK signaling pathway. Upregulated (MMP2, JUN, KAT28, and PIK3R3) and downregulated genes (CXCL8, CCND1, IGF1R, and ITGB3) were considered as hub genes in the PPI network. Additionally, PIK3R3 and LEF1 served as key genes in the regulatory network. The overexpression of MMP2 and CXCL8 was associated with a poor prognosis in melanoma patients.
Conclusion: MMP2, CXCL8, PIK3R3, ITGB3, and LEF1 may play roles in the efficacy of vemurafenib treatment in melanoma; for example, MMP2 and PIK3R3 are likely associated with vemurafenib resistance. These findings will contribute to the development of novel therapies for melanoma.
Combinatorial Chemistry & High Throughput Screening