Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026
S100A10 promotes glycolysis and malignant progression of CCA by activating the HK2/ERK signaling pathway.
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Wang Yajun, Chen Wenjie, Liu Wei, Zhang Xu, Wang Yongxing, Dai Niu
Аннотация
BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a highly aggressive malignancy characterized by late diagnosis and poor prognosis. The molecular mechanisms driving CCA progression and metabolic reprogramming remain incompletely understood. This study aimed to elucidate the clinical significance, biological function, and underlying mechanisms of the calcium-binding protein S100A10 in CCA pathogenesis.
METHODS: S100A10 expression was analyzed using TCGA and Human Protein Atlas datasets and validated in a clinical cohort of 46 CCA patients. The diagnostic value and prognostic associations were evaluated statistically. Loss-of-function assays (shRNA knockdown) were performed in HuCCT1 cells to assess proliferation, migration, invasion, and apoptosis. Mechanistic investigations involved metabolic assays (glucose uptake/lactate release), Western blotting, and rescue experiments targeting the Hexokinase 2 (HK2) and ERK signaling pathways.
RESULTS: Bioinformatic analysis and clinical validation revealed that S100A10 is significantly upregulated in CCA tissues compared to normal controls, with a high diagnostic accuracy (AUC = 0.917). Elevated S100A10 expression correlated significantly with advanced tumor stage and shortened overall survival. Functionally, S100A10 silencing markedly attenuated CCA cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, S100A10 was found to orchestrate metabolic reprogramming by enhancing aerobic glycolysis. This effect was mediated through the regulation of key glycolytic enzymes, particularly HK2, and the activation of the ERK signaling cascade. Notably, the suppression of malignant phenotypes induced by S100A10 depletion was partially reversed by either HK2 overexpression or pharmacological ERK activation.
CONCLUSIONS: This study identifies S100A10 as a critical oncogenic driver in CCA that links metabolic reprogramming to tumor progression via the HK2/ERK signaling axis. These findings suggest S100A10 is a robust prognostic biomarker and a potential therapeutic target for disrupting the metabolic adaptability of cholangiocarcinoma.
METHODS: S100A10 expression was analyzed using TCGA and Human Protein Atlas datasets and validated in a clinical cohort of 46 CCA patients. The diagnostic value and prognostic associations were evaluated statistically. Loss-of-function assays (shRNA knockdown) were performed in HuCCT1 cells to assess proliferation, migration, invasion, and apoptosis. Mechanistic investigations involved metabolic assays (glucose uptake/lactate release), Western blotting, and rescue experiments targeting the Hexokinase 2 (HK2) and ERK signaling pathways.
RESULTS: Bioinformatic analysis and clinical validation revealed that S100A10 is significantly upregulated in CCA tissues compared to normal controls, with a high diagnostic accuracy (AUC = 0.917). Elevated S100A10 expression correlated significantly with advanced tumor stage and shortened overall survival. Functionally, S100A10 silencing markedly attenuated CCA cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, S100A10 was found to orchestrate metabolic reprogramming by enhancing aerobic glycolysis. This effect was mediated through the regulation of key glycolytic enzymes, particularly HK2, and the activation of the ERK signaling cascade. Notably, the suppression of malignant phenotypes induced by S100A10 depletion was partially reversed by either HK2 overexpression or pharmacological ERK activation.
CONCLUSIONS: This study identifies S100A10 as a critical oncogenic driver in CCA that links metabolic reprogramming to tumor progression via the HK2/ERK signaling axis. These findings suggest S100A10 is a robust prognostic biomarker and a potential therapeutic target for disrupting the metabolic adaptability of cholangiocarcinoma.