Chun-Wei Liu, Jing-Hui Huang, Hsiu-Hao Chang, Chia-Hua Chen, Yi-Huan Tsai, Wei-Li Chen, Jung-An Lin, Hsiu-Ling Chang, Cheng-Chang Chen, Mei-Chun Lin, Min-Chuan Huang, Neng-Yu Lin
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Abstract
Osteosarcoma is an aggressive bone malignancy with a high propensity for drug resistance and metastasis, leading to poor clinical outcomes. This study investigates the role of core 1 β1,3-galactosyltransferase 1 (C1GALT1) in osteosarcoma, focusing on its implications in chemoresistance. Our findings reveal that high expression of C1GALT1 is associated with advanced stages, adverse overall survival, and increased recurrence rates. Elevated levels of C1GALT1 were observed in doxorubicin-selected osteosarcoma cells, where its suppression significantly promoted doxorubicin-induced apoptosis and reduced drug efflux. Pharmacological inhibition of C1GALT1 using itraconazole replicated these effects, suggesting a potential therapeutic strategy to overcome chemoresistance. Additionally, we identified the involvement of the ATP-binding cassette (ABC) transporter ABCC1 in the drug-resistance phenotype mediated by C1GALT1. C1GALT1-mediated O-glycan changes were found to influence the cell-surface targeting and lysosomal degradation of ABCC1, thereby modulating its efflux capacity. In vitro and in vivo studies confirmed that C1GALT1 impacts ABCC1 expression and function, further supporting its role in osteosarcoma chemoresistance. These results highlight the clinical relevance of C1GALT1 as a biomarker for prognosis and a potential therapeutic target for osteosarcoma. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
C1GALT1的表达预示着骨肉瘤的低生存率,并且对于ABCC1转运蛋白介导的阿霉素耐药性至关重要。
骨肉瘤是一种侵袭性骨恶性肿瘤,具有较高的耐药和转移倾向,导致临床预后较差。本研究探讨了核心1 β1,3-半乳糖转移酶1 (C1GALT1)在骨肉瘤中的作用,重点研究了其在化疗耐药中的意义。我们的研究结果表明,C1GALT1的高表达与晚期、不良的总生存期和复发率增加有关。在阿霉素选择的骨肉瘤细胞中观察到C1GALT1水平升高,其抑制可显著促进阿霉素诱导的细胞凋亡并减少药物外排。使用伊曲康唑对C1GALT1进行药理学抑制可复制这些效应,提示克服化疗耐药的潜在治疗策略。此外,我们发现atp结合盒(ABC)转运体ABCC1参与了C1GALT1介导的耐药表型。发现c1galt1介导的o -聚糖变化影响ABCC1的细胞表面靶向和溶酶体降解,从而调节其外排能力。体外和体内研究证实,C1GALT1影响ABCC1的表达和功能,进一步支持其在骨肉瘤化疗耐药中的作用。这些结果突出了C1GALT1作为预后生物标志物和骨肉瘤潜在治疗靶点的临床相关性。©2025作者。《病理学杂志》由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
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