Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Buenos Aires, Argentina and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Maimónides, Hidalgo 775, 6th Floor, Lab 602, 1405, Buenos Aires, Argentina.
Med Oncol. 2022 Jul 14;39(10):141. doi: 10.1007/s12032-022-01734-8.
Several diagnostic and prognostic markers for melanoma have been identified in last few years. However, their actual contribution to melanoma progression have not been investigated in detail. This study was aimed to identify genes, biological processes, and signaling pathways implicated in melanoma progression by applying bioinformatics analysis. We identified nine differentially expressed genes (DEGs) (IL36RN, KRT6A, KRT6B, KRT16, S100A7, SPRR1A, SPRR1B, SPRR2B, and KLK7) that were upregulated in primary melanoma compared with metastatic melanoma in all five datasets analyzed. All these genes except IL36RN, both form a protein-protein interaction network and have cellular functions associated with constitutive processes of keratinocytes. Thus, they were generically termed Epidermal Development and Cornification (EDC) genes. The differential expression of these genes in primary and metastatic melanoma was confirmed in the TCGA-SKCM cohort. High expression of the EDC genes correlated with reduced tumor thickness in primary melanoma and shorter survival in metastatic melanoma. Analysis of DEGs from primary melanoma patients displaying high or low expression of all eight EDC revealed that the upregulated genes are enriched in biological process related to cell migration, extracellular matrix organization, invasion, and Epithelial-Mesenchymal Transition. Further analysis of enriched curated oncogenic genesets together with RPPA data of phosphorylated proteins revealed the activation of MEK, ATF2, and EGFR pathways in tumors displaying high expression of EDC genes. Thus, EDC genes may contribute to melanoma progression by promoting the activation of MEK, ATF2, and EGFR pathways together with biological processes associated with tumor aggressiveness.
近年来，已经确定了几种用于黑色素瘤的诊断和预后标志物。然而，它们对黑色素瘤进展的实际贡献尚未详细研究。本研究旨在通过应用生物信息学分析来鉴定与黑色素瘤进展相关的基因、生物过程和信号通路。我们鉴定了九个差异表达基因（DEGs）（IL36RN、KRT6A、KRT6B、KRT16、S100A7、SPRR1A、SPRR1B、SPRR2B 和 KLK7），这些基因在所有五个分析的数据集的原发性黑色素瘤中均比转移性黑色素瘤高表达。除了 IL36RN 之外，所有这些基因都形成了一个蛋白质-蛋白质相互作用网络，并且具有与角质形成细胞的组成过程相关的细胞功能。因此，它们通常被称为表皮发育和角化（EDC）基因。这些基因在 TCGA-SKCM 队列中的原发性和转移性黑色素瘤中的差异表达得到了证实。EDC 基因的高表达与原发性黑色素瘤中肿瘤厚度的降低和转移性黑色素瘤中生存时间的缩短相关。对显示所有八个 EDC 高或低表达的原发性黑色素瘤患者的 DEGs 进行分析表明，上调基因富集在与细胞迁移、细胞外基质组织、侵袭和上皮-间充质转化相关的生物学过程中。对富含 curated 致癌基因集的进一步分析以及磷酸化蛋白的 RPPA 数据表明，在 EDC 基因高表达的肿瘤中 MEK、ATF2 和 EGFR 途径被激活。因此，EDC 基因可能通过促进 MEK、ATF2 和 EGFR 途径的激活以及与肿瘤侵袭性相关的生物学过程来促进黑色素瘤的进展。
