| Summary: | Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant hepatic tumor and has a high postoperative recurrence rate and a poor prognosis. The key roles of most tumor recurrence-associated molecules in iCCA remain unclear. This study aimed to explore hub genes related to the postsurgical recurrence of iCCA. Method Differentially expressed genes (DEGs) between iCCA samples and normal liver samples were screened from The Cancer Genome Atlas (TCGA) database and used to construct a weighted gene coexpression network. Module-trait correlations were calculated to identify the key module related to recurrence in iCCA patients. Genes in the key module were subjected to functional enrichment analysis, and candidate hub genes were filtered through coexpression and protein–protein interaction (PPI) network analysis. Validation studies were conducted to detect the “real” hub gene. Furthermore, the biological functions and the underlying mechanism of the real hub gene in iCCA tumorigenesis and progression were determined via in vitro experiments. Results A total of 1019 DEGs were filtered and used to construct four coexpression modules. The red module, which showed the highest correlations with the recurrence status, family history, and day to death of patients, was identified as the key module. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that genes in the red module were enriched in genes and pathways related to tumorigenesis and tumor progression. We performed validation studies and identified estrogen receptor 1 (ESR1), which significantly impacted the prognosis of iCCA patients, as the real hub gene related to the recurrence of iCCA. The in vitro experiments demonstrated that ESR1 overexpression significantly suppressed cell proliferation, migration, and invasion, whereas ESR1 knockdown elicited opposite effects. Further investigation into the mechanism demonstrated that ESR1 acts as a tumor suppressor by inhibiting the JAK/STAT3 signaling pathway. Conclusions ESR1 was identified as the real hub gene related to the recurrence of iCCA that plays a critical tumor suppressor role in iCCA progression. ESR1 significantly impacts the prognosis of iCCA patients and markedly suppresses cholangiocarcinoma cell proliferation, migration and invasion by inhibiting JAK/STAT3 signaling pathway.
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