An in silico toxicogenomic approach in constructing the aflatoxin B1-mediated regulatory network of hub genes in hepatocellular carcinoma

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.

Automated summary

By analyzing toxicogenomic data, we inferred the molecular pathway network involved in hepatocellular carcinoma (HCC) induced by aflatoxin B1 (AFB1). Computational tools were utilized to identify protein-protein interaction network, hub genes, transcription factors (TFs), upstream kinases, and biological processes (BPs). Our results revealed an association between AFB1 and hub genes involved in the cell cycle, and we identified TFs that regulate these hub genes and linked them with upstream kinases. This study provides important insights into the signaling hierarchy and information flow contributing to AFB1-induced HCC.