Department of Biology and Ecology, University of Novi Sad, Novi Sad, Serbia.
Department of Mathematics and Informatics, University of Novi Sad, Novi Sad, Serbia.
Toxicol Mech Methods. 2023 Sep;33(7):552-562. doi: 10.1080/15376516.2023.2196686. Epub 2023 Apr 9.
Aflatoxin B1 (AFB1) can cause hepatocellular carcinoma (HCC) through a mutagenic mode of action but can also lead to global changes in gene expression; however, the AFB1 network of molecular pathways involved in HCC is not known. Here, we used toxicogenomic data from human liver cells exposed to AFB1 to infer the network of AFB1-responsive molecular pathways involved in HCC. The following computational tools: STRING, MCODE, cytoHubba, iRegulon, kinase enrichment tool KEA3, and DAVID were used to identify protein-protein interaction network, hub genes, transcription factors (TFs), upstream kinases, and biological processes (BPs). Predicted molecular events were validated with an external dataset, whereas the hub genes in HCC were validated using the UALCAN database. The results revealed an association between AFB1 and the hub genes involved in the cell cycle. We identified TFs that regulate the hub genes and linked them with upstream kinases including cyclin-dependent kinases, mitogen-activated protein kinase 1, and AKT. This approach enabled the construction of the AFB1-mediated regulatory network consisting of upstream kinases, TFs, hub genes, and BPs, thus revealing the signaling hierarchy and information flow that may contribute to AFB1-induced HCC. This could be a useful tool in predicting the molecular mechanisms involved in chemical-induced diseases when available toxicogenomic data exist.
黄曲霉毒素 B1（AFB1）可以通过致突变作用模式导致肝细胞癌（HCC），但也可以导致基因表达的全局变化；然而，参与 HCC 的 AFB1 分子途径网络尚不清楚。在这里，我们使用人类肝细胞暴露于 AFB1 的毒理基因组学数据来推断参与 HCC 的 AFB1 反应分子途径的网络。使用以下计算工具：STRING、MCODE、cytoHubba、iRegulon、激酶富集工具 KEA3 和 DAVID 来识别蛋白质-蛋白质相互作用网络、枢纽基因、转录因子（TFs）、上游激酶和生物过程（BP）。使用外部数据集验证预测的分子事件，而 HCC 中的枢纽基因则使用 UALCAN 数据库进行验证。结果表明 AFB1 与细胞周期中涉及的枢纽基因之间存在关联。我们鉴定了调节枢纽基因的 TFs，并将它们与包括细胞周期蛋白依赖性激酶、丝裂原活化蛋白激酶 1 和 AKT 在内的上游激酶联系起来。这种方法能够构建由上游激酶、TFs、枢纽基因和 BP 组成的 AFB1 介导的调控网络，从而揭示可能导致 AFB1 诱导的 HCC 的信号级联和信息流。当存在可用的毒理基因组学数据时，这可能是预测化学诱导疾病涉及的分子机制的有用工具。
