Tumor metastasis is the most common recurrence mode and cause of death in SKCM, which seriously affects patient survival and prognosis. Thus, it is urgent to better understand the molecular mechanisms of metastasis and explore effective indicators for monitoring this pathophysiological process.
In the present study, we identified 294 genes that were closely related to melanoma metastasis. GO analysis showed that DEGs were mainly enriched in the positive regulation of locomotion, mitotic cell cycle process, epithelial cell differentiation, and actin filament-based process. The above biological processes are mainly related to cell movement and cell proliferation. We speculate that DEGs induced melanoma cell metastasis by promoting cell migration and cell proliferation. KEGG enrichment analysis revealed that DEGs were mainly enriched pathways in cancer, microRNAs in cancer, phospholipase D signaling pathway, and purine metabolism. Phospholipase D is an enzyme that catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid. Studies have found that the phospholipase D signaling pathway is involved in lung cancer-mediated bone metastasis, and phospholipase D isoform 1 promotes tumor invasion of bladder cancer by regulating MMP-13 expression.The role of the phospholipase D signaling pathway in melanoma metastasis is worth further exploration.
Next, we screened 4 specific metastasis-associated genes by conducting a PPI network and analyzed their prognostic value though the TCGA database. The results suggest that CDK1 and FOXM1 may be favorable predictive factors for melanoma patient survival. FOXM1 is a regulator of myriad biological processes, including cell proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis and apoptosis, and has been suggested to be a key player in tumorigenesis . Moreover, FOXM1 is a known downstream factor of the Akt signaling cascade [22, 23], and inactivation of the Akt/FOXM1 signaling pathway may suppress the proliferation and metastasis of gastric cancer cells . In our present study, we found that FOXM1 expression was not significantly different between metastatic melanoma tissues and primary melanoma tissues, and FOXM1 seemed not to be a potential metastasis-associated biomarker for melanoma. We therefore further researched the CDK1 gene, which is specifically involved in the metastasis process of melanoma and predicts a poor prognosis.
CDK1, namely, cyclin-dependent kinase 1, is a serine/threonine-like protein kinase and plays critical roles in the regulation of the cell cycle and cell proliferation. Previous studies have reported that CDK1 forms a complex with cyclin A/B that is involved in the regulation of mitosis, G2/M checkpoint maintenance, execution of apoptosis, maintenance of pluripotency and genomic stability . Furthermore, CDK1 has been revealed to be overexpressed in various malignancies. High expression of CDK1 may lead to poor clinical prognosis, and inhibition of CDK1 enhances 5-Fu sensitivity in colorectal cancer . Z. Huang et al. reported that CDK1 positively regulated the stemness of lung cancer cells in a Sox2-dependent manner, and inhibition of CDK1 enhanced chemotherapeutic sensitivity in lung cancer . Recently, CDK1-mediated phosphorylation of TFCP2L1 has been shown to be required for stem cell pluripotency and bladder carcinogenesis. CDK1 interacts with Sox2 and promotes tumor initiation in human melanoma. The role of CDK1 in melanoma metastasis has not been reported previously.
The tumor microenvironment (TME) is composed of immune cells, mesenchymal cells, endothelial cells, inflammatory mediators and extracellular matrix (ECM) molecules [30, 31]. The composition and abundance of immune cells in the tumor microenvironment strongly influence the progression of tumors and the effect of immunotherapy [32-34]. We found that the expression levels of CDK1 were correlated with immune cell infiltration. We speculate that CDK1 is involved in the process of melanoma metastasis by regulating the function of the tumor microenvironment. Therefore, the function and pathway of CDK-mediated immune cell-infiltration need to be further investigated.
Currently, according to the genotype and stage of melanoma, targeted therapy, such as BRAF inhibitors and MEK inhibitors, has been used as first-line treatment or adjuvant therapy for patients . In 2011, the FDA approved the first targeted therapeutic drug for advanced BRAF-mutant melanoma, vemurafenib . In this study, ten drugs were identified, that may serve as potential therapeutic targets. Rucaparib, as a PAPP inhibitor, has been approved by the FDA for the clinical treatment of ovarian cancer . In a phase II study, temozolomide (150–200 mg/m(2)/day) was safely given with rucaparib, increasing progression-free survival over historical controls in patients with advanced metastatic melanoma. Dinaciclib induces p53 expression while simultaneously downregulating the expression of the antiapoptotic factors Mcl-1 and XIAP in melanoma cell lines . The small-molecule drug AT-7519 diminished MDM4 levels and activated p53 in the A375 melanoma cell line . Other drugs have not been reported in the literature for the treatment of melanoma metastasis.
The main limitation of our study was only the analysis of bioinformatics, so it was urgent to carry out cytological experiments, animal experiments, and drug trials to verify these hub genes in melanoma metastasis.