最近的研究表明,砷诱导的细胞恶性转化涉及复杂的机制。本研究旨在破译与砷诱导的皮肤鳞状细胞癌(cSCC)相关的分子机制,并提出潜在的保护因素。使用暴露于砷的人角质形成细胞(HaCaT)和对照之间基于RNAseq的差异表达基因来构建蛋白质-蛋白质相互作用(PPI)网络并发现关键的基于子网络的机制。确定了针对砷毒性的保护性化合物,并通过比较毒性基因组数据库(CTD)确定了它们在核心子网络中的目标相互作用。通过分子对接计算有效因子与靶标之间的结合亲和力。共筛选出15个关键蛋白作为关键砷响应子网络(FN1、IL-1A、CCN2,PECAM1,FGF5,EDN1,FGF1,PXDN,DNAJB9,XBP1,ERN1,PDIA4,DNAJB11,FOS,PDIA6)和7种有效的保护剂(叶酸,槲皮素,锌,乙酰半胱氨酸,蛋氨酸,儿茶素,硒)。GeneMANIA预测了子网的详细相互作用,并揭示了与未折叠蛋白质反应相关的术语作为主要过程。FN1、IL1A和CCN2作为最重要的基因,与叶酸、槲皮素有良好的对接亲和力,作为选定的关键化合物。cSCC中与砷暴露相关的基因表达和蛋白质-蛋白质相互作用的整合探索了潜在的机制和保护剂。
Recent studies show that complex mechanisms are involved in arsenic-induced malignant transformation of cells. This study aimed to decipher molecular mechanisms associated with arsenic-induced cutaneous squamous cell carcinoma (cSCC) and suggest potential protective factors. RNA-seq-based differentially expressed genes between arsenic-exposed human keratinocytes (HaCaT) and controls were used to construct a protein-protein interaction (PPI) network and discover critical subnetwork-based mechanisms. Protective compounds against arsenic toxicity were determined and their target interactions in the core sub-network were identified by the comparative toxicogenomic database (CTD). The binding affinity between the effective factor and target was calculated by molecular docking. A total of 15 key proteins were screened out as critical arsenic-responsive subnetwork (FN1, IL-1A, CCN2, PECAM1, FGF5, EDN1, FGF1, PXDN, DNAJB9, XBP1, ERN1, PDIA4, DNAJB11, FOS, PDIA6) and 7 effective protective agents were identified (folic acid, quercetin, zinc, acetylcysteine, methionine, catechin, selenium). The GeneMANIA predicted detailed interactions of the subnetwork and revealed terms related to unfolded protein response as the main processes. FN1, IL1A and CCN2, as top significant genes, had good docking affinity with folic acid and quercetin, as selected key compounds. Integration of gene expression and protein-protein interaction related to arsenic exposure in cSCC explored the potential mechanisms and protective agents.