Department of Traumatology, Guizhou Province, Tongren People's Hospital, No 120 Middle Section of Taoyuan Avenue, Tongren City, 554399, People's Republic of China.
Naunyn Schmiedebergs Arch Pharmacol. 2023 Oct;396(10):2427-2447. doi: 10.1007/s00210-023-02461-1. Epub 2023 Apr 22.
Skin cutaneous melanoma (SKCM) has a low early detection rate and a high mortality rate. There are many problems such as side effects and drug resistance in existing therapeutic drugs. Current studies have confirmed that SKCM pathogenesis-related genes promote the invasion and metastasis of cutaneous melanoma, but their roles in the tumor microenvironment (TME) remain unclear. Network pharmacology provides new opportunities for drug repurposing and repositioning, and is a fast, safe, and inexpensive drug discovery method to find new drugs for the treatment of SKCM. In this study, based on 3 databases (KEGG, OMIM, and Genotype) to obtain SKCM-related genes, and TCGA SKCM dataset, SKCM differential genes in GSE3189 and GSE46517 were intersected to identify SKCM pathogenesis-related differential genes, and the differential genes were immune infiltration and analysis, For survival analysis, a prognostic nomogram risk model was constructed based on the results of multivariate Cox regression analysis for risk stratification and prognosis prediction, then focused on the differential expression of ZC3H12A and its effect on TME. Finally, the protein interaction network method was used to quantify the similarity between 684 drug targets and skin melanoma, and to screen out drugs similar to skin melanoma. Based on 3 databases of KEGG, OMIM, and Genotype, 294 SKCM-related genes and 18 SKCM pathogenesis-related differential genes were obtained, and 18 SKCM pathogenesis-related differential genes were significantly correlated with TME. The constructed prognostic nomogram risk model predicted performance better and provided valuable information for immunotherapy. Multivariate Cox regression analysis and K-M analysis showed that ZC3H12A was a differentially expressed gene affecting the prognosis of SKCM and promoted the infiltration of anti-tumor immune cells CD8 + T cells, B cells, and DC cells. Based on the analysis of the protein interaction network method, 43 drugs were found to have high potential in the treatment of SKCM, and the literature search of these 43 drugs was carried out, and 21 drugs were found to have experimental verification for the treatment of SKCM. Taken together, the differential genes associated with the pathogenesis of SKCM have important roles in the tumor immune microenvironment, clinicopathological features, and prognosis, especially ZC3H12A has a potential role in identifying early SKCM patients. At the same time, it provides a new strategy for the drug development of SKCM and provides a basis for the reuse of SKCM drugs.
皮肤黑色素瘤 (SKCM) 的早期检测率低，死亡率高。现有的治疗药物存在副作用和耐药性等诸多问题。目前的研究已经证实，SKCM 发病相关基因促进黑色素瘤的侵袭和转移，但它们在肿瘤微环境（TME）中的作用尚不清楚。网络药理学为药物再利用和重新定位提供了新的机会，是一种快速、安全、廉价的药物发现方法，可寻找治疗 SKCM 的新药。本研究基于 3 个数据库（KEGG、OMIM 和 Genotype）获得 SKCM 相关基因，以及 TCGA SKCM 数据集，通过交集得到 SKCM 差异基因，对 SKCM 差异基因进行免疫浸润分析和生存分析，基于多因素 Cox 回归分析结果构建预后列线风险模型进行风险分层和预后预测，然后聚焦于 ZC3H12A 的差异表达及其对 TME 的影响。最后，采用蛋白质相互作用网络方法量化 684 个药物靶点与皮肤黑色素瘤的相似性，筛选出与皮肤黑色素瘤相似的药物。基于 KEGG、OMIM 和 Genotype 这 3 个数据库，共获得 294 个 SKCM 相关基因和 18 个 SKCM 发病相关差异基因，且 18 个 SKCM 发病相关差异基因与 TME 呈显著相关性。构建的预后列线风险模型预测性能更好，为免疫治疗提供了有价值的信息。多因素 Cox 回归分析和 K-M 分析显示，ZC3H12A 是影响 SKCM 预后的差异表达基因，并促进抗肿瘤免疫细胞 CD8+T 细胞、B 细胞和 DC 细胞的浸润。通过蛋白质相互作用网络方法分析，发现 43 种药物在治疗 SKCM 方面具有较高的潜力，并对这 43 种药物进行文献检索，发现其中 21 种药物在治疗 SKCM 方面有实验验证。综上所述，与 SKCM 发病机制相关的差异基因在肿瘤免疫微环境、临床病理特征和预后中具有重要作用，尤其是 ZC3H12A 在识别早期 SKCM 患者方面具有潜在作用。同时，为 SKCM 药物的开发提供了新策略，为 SKCM 药物的再利用提供了依据。
