Abstract
Development of hepatocellular carcinoma (HCC) is a dynamic process that includes a spectrum ranging from precancerous exposure to carcinogenesis and metastasis stages. In this process, numerous dysregulated genes resulted in aberrant activation or inhibition of signaling pathways. Herein, time-series gene expression profiles of dimethylnitrosamine (DEN)-induced mice with HCC covering different stages are provided. Gene expression patterns of liver tissues were detected at different time intervals [0 (negative control; NC), 15, 28, 30, and 42 weeks]. A comparison of gene expression between DEN-treated groups and NC yielded a total of 726 differentially expressed genes (DEGs), 76 of which were enriched in 10 statistically significant Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways (adjusted p value <0.05). After assessing regulation among these cascades, we found that Stat3 was a crucial transcription factor. Additionally, it was a connector in the PPI network constituting the 76 DEGs. Western blotting and immunohistochemistry suggested that the phosphorylation of Stat3 at tyrosine 705 (pStat3 Y705) was down-regulated in early stage HCC. Following, survival analysis revealed that patients with down-regulated pSTAT3 Y705 exhibited reduced overall survival rates in both the early stage and well-differentiated groups (p=0.00022 and p=0.0026, respectively). This is the first study evaluating dynamic gene expression profiles in a time-series DEN-induced mouse HCC model. Stat3 was identified as a crucial node during HCC progression, and pSTAT3 Y705 serves as a prognostic biomarker for early-stage HCC.