Abubakari Sumaila, Dizman Yeşim Aktürk, Karaman Filiz
Department of Statistics, Faculty of Arts and Science, Yildiz Technical University, Davutpaşa Campus, 34220 İstanbul, Türkiye.
Department of Biology, Faculty of Arts and Sciences, Recep Tayyip Erdoğan University, 53100 Rize, Türkiye.
Diagnostics (Basel). 2025 Jul 13;15(14):1770. doi: 10.3390/diagnostics15141770.
Cutaneous melanoma is one of the aggressive forms of skin cancer originating from melanocytes. The high incidence of melanoma metastasis continues to rise, partly due to the complex nature of the molecular mechanisms driving its progression. While melanomas generally arise from melanocytes, we investigated whether aberrant keratinocyte differentiation pathways-like cornified envelope formation-discriminate primary melanoma from metastatic melanoma, revealing novel biomarkers in progression. In the present study, we retrieved four datasets (GSE15605, GSE46517, GSE8401, and GSE7553) associated with primary and metastatic melanoma tissues and identified differentially expressed genes (DEGs). Thereafter, an integrated meta-analysis and functional enrichment analysis of the DEGs were performed to evaluate the molecular mechanisms involved in melanoma metastasis, such as immune cell deconvolution and protein-protein interaction (PPI) network construction. Hub genes were identified based on four topological methods, including 'Betweenness', 'MCC', 'Degree', and 'Bottleneck'. We validated the findings using the TCGA-SKCM cohort. Drug-gene interactions were evaluated using the DGIdb, whereas structural druggability was assessed using the ProteinPlus and AlphaFold databases. We identified a total of eleven hub genes associated with melanoma progression. These included members of the keratin gene family (e.g., KRT5, KRT6A, KRT6B, etc.). Except for the gene CDH1, all the hub genes were downregulated in metastatic melanoma tissues. From a prognostic perspective, these hub genes were associated with poor prognosis (i.e., unfavorable). Using the Human Protein Atlas (HPA), immunohistochemistry evaluation revealed mostly undetected levels in metastatic melanoma. Additionally, the cornified envelope formation was the most enriched pathway, with a gene ratio of 17/33. The tumor microenvironment (TME) of metastatic melanomas was predominantly enriched in NK cell-associated signatures. Finally, several hub genes demonstrated favorable druggable potential for immunotherapy. Through integrated meta-analysis, this study identifies transcriptional, immunological, and structural pathways to melanoma metastasis and highlights keratin family genes as promising biomarkers for therapeutic targeting.
皮肤黑色素瘤是源自黑素细胞的侵袭性皮肤癌形式之一。黑色素瘤转移的高发病率持续上升，部分原因是驱动其进展的分子机制具有复杂性。虽然黑色素瘤通常起源于黑素细胞，但我们研究了异常的角质形成细胞分化途径（如角质包膜形成）是否能区分原发性黑色素瘤和转移性黑色素瘤，从而揭示进展过程中的新型生物标志物。在本研究中，我们检索了与原发性和转移性黑色素瘤组织相关的四个数据集（GSE15605、GSE46517、GSE8401和GSE7553），并鉴定了差异表达基因（DEG）。此后，对DEG进行了综合荟萃分析和功能富集分析，以评估参与黑色素瘤转移的分子机制，如免疫细胞反卷积和蛋白质-蛋白质相互作用（PPI）网络构建。基于四种拓扑方法（包括“介数”、“MCC”、“度”和“瓶颈”）鉴定了枢纽基因。我们使用TCGA-SKCM队列验证了研究结果。使用DGIdb评估药物-基因相互作用，而使用ProteinPlus和AlphaFold数据库评估结构可成药性。我们总共鉴定了11个与黑色素瘤进展相关的枢纽基因。这些基因包括角蛋白基因家族的成员（如KRT5、KRT6A、KRT6B等）。除了CDH1基因外，所有枢纽基因在转移性黑色素瘤组织中均下调。从预后角度来看，这些枢纽基因与预后不良（即不利）相关。使用人类蛋白质图谱（HPA），免疫组织化学评估显示转移性黑色素瘤中大多检测不到这些基因的水平。此外，角质包膜形成是最富集的途径，基因比例为17/33。转移性黑色素瘤的肿瘤微环境（TME）主要富集于自然杀伤细胞相关特征。最后，几个枢纽基因显示出对免疫治疗有利的可成药潜力。通过综合荟萃分析，本研究确定了黑色素瘤转移的转录、免疫和结构途径，并突出了角蛋白家族基因作为有前景的治疗靶点生物标志物。
