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Expression characteristics, targeted regulation, and synergistic mechanisms of IGF2BP3 and UXS1 in hepatocellular carcinoma
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Abstract:
[Abstract] Objective: To investigate the expression characteristics and prognostic significance of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and the uridine diphosphate-glucuronate decarboxylase 1 (UXS1) as well as the molecular mechanisms of the synergistic interaction between them in hepatocellular carcinoma (HCC). Methods: Transcriptomic data from multiple public databases, including UALCAN, cBioPortal, ENCORI, TISCH2, and GDSC were integrated to analyze the expressions, prognosis, functional enrichment, and drug sensitivity of IGF2BP3 and UXS1. Single-cell RNA sequencing (scRNA-seq) data from the GEO repository were further collected to examine cell-cell communication and single-cell metabolic activity, thereby systematically analyzing the specific function of the IGF2BP3- UXS1 axis in HCC. Results: The expressions of IGF2BP3 and UXS1 were significantly upregulated in HCC tissues, and high expressions of either gene were associated with markedly shorter overall survival (both P < 0.05). CRISPR-mediated knockout of IGF2BP3 or UXS1 substantially suppressed the proliferative capacity of multiple HCC cell lines. scRNA-seq analysis revealed broad expressions of both genes across hepatic cell population: IGF2BP3 expression was upregulated during late-stage hepatocyte differentiation, whereas UXS1 was highly expressed during early and mid differentiation stages. High expressions of IGF2BP3 or UXS1 significantly activated the MIF signaling pathway. Elevated expression of IGF2BP3 weakened the interactions between fibroblast-tumor cells, while high expression of UXS1 enhanced T-cell signal transduction. A significant positive correlation was observed between the expressions of IGF2BP3 and UXS1 (r = 0.432, P < 0.05). Silencing of the IGF2BP3 binding site resulted in changes in UXS1 expression levels (F = 0.333). Functional enrichment analyses indicated that IGF2BP3 and UXS1 synergistically regulated key biological processes, including energy metabolism and protein translation. Moreover, both genes showed strong associations with multiple glycometabolic pathways in high-expression tumor subpopulations. Patients with high IGF2BP3 or UXS1 expressions exhibited heightened sensitivity to uprosertib and pronounced resistance to navitoclax. Conclusion: IGF2BP3 and UXS1 are highly expressed in HCC. Both genes promote malignant biological behaviors of HCC by regulating coordinated reprogramming of glucose metabolism.
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