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ObjectiveCholangiocarcinoma is a lethal malignancy with an increasing incidence and mortality worldwide. Numerous studies have indicated that high-mobility group box 1 is associated with cancer progression. The modulation of subcellular high-mobility group box 1 expression is a major cause of chemotherapeutic drug resistance. This study aimed to demonstrate the role of high-mobility group box 1 in cholangiocarcinoma, including proving the concept of high-mobility group box 1 expression in patients with cholangiocarcinoma, cancer cell growth, migration, invasion, and the modulation of chemotherapeutic drug sensitivity in cholangiocarcinoma cells.MethodsTwenty paraffin-embedded tissue samples were analyzed for high-mobility group box 1 expression using immunohistochemistry. High-mobility group box 1 expression was silenced in KKU-213AL5 cells through siRNA transfection, followed by in vitro assays to assess cell proliferation, migration, invasion, and drug sensitivity. Furthermore, the role of high-mobility group box 1 in regulating growth and metastasis-related signaling pathways was investigated using immunoblotting and protein-protein interaction analysis.ResultsThe results showed that high-mobility group box 1 was highly expressed in cholangiocarcinoma tissues compared to adjacent tissues (p-value < 0.001), as well as the HMGB1 expression analysis from the TCGA database. Silencing high-mobility group box 1 by siRNA transfection resulted in the reduction of cholangiocarcinoma cell growth, migration, and invasion. Interestingly, high-mobility group box 1 silencing enhanced sensitivity to Gemcitabine and Cisplatin by increasing cell cytotoxicity compared to transfection control (p-value = 0.0002 and 0.0258, respectively). We further demonstrated that reduction of high-mobility group box 1 expression attenuates the essential signaling proteins, including Akt, Erk, and cyclin D1, which are crucial in cancer cell growth and metastasis signaling pathways.ConclusionsThis study demonstrates that high-mobility group box 1 plays a critical role in cholangiocarcinoma proliferation, migration and invasion, and may serve as a diagnostic biomarker. Targeting high-mobility group box 1 could enhance therapeutic outcomes, particularly in overcoming drug resistance.