Laboratorio de Microambiente Tumoral, Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires, Junín 6000, Argentina.
Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CITNOBA), UNNOBA-UNSAdA-CONICET, Junín 6000, Argentina.
Biomolecules. 2021 Feb 9;11(2):246. doi: 10.3390/biom11020246.
UDP-glucose-dehydrogenase (UGDH) synthesizes UDP-glucuronic acid. It is involved in epirubicin detoxification and hyaluronan synthesis. This work aimed to evaluate the effect of UGDH knockdown on epirubicin response and hyaluronan metabolism in MDA-MB-231 breast cancer cells. Additionally, the aim was to determine UGDH as a possible prognosis marker in breast cancer. We studied UGDH expression in tumors and adjacent tissue from breast cancer patients. The prognostic value of UGDH was studied using a public Kaplan-Meier plotter. MDA-MB-231 cells were knocked-down for UGDH and treated with epirubicin. Epirubicin-accumulation and apoptosis were analyzed by flow cytometry. Hyaluronan-coated matrix and metabolism were determined. Autophagic-LC3-II was studied by Western blot and confocal microscopy. Epirubicin accumulation increased and apoptosis decreased during UGDH knockdown. Hyaluronan-coated matrix increased and a positive modulation of autophagy was detected. Higher levels of UGDH were correlated with worse prognosis in triple-negative breast cancer patients that received chemotherapy. High expression of UGDH was found in tumoral tissue from HER2-patients. However, UGDH knockdown contributes to epirubicin resistance, which might be associated with increases in the expression, deposition and catabolism of hyaluronan. The results obtained allowed us to propose UGDH as a new prognostic marker in breast cancer, positively associated with development of epirubicin resistance and modulation of extracellular matrix.
UDP-葡萄糖脱氢酶 (UGDH) 合成 UDP-葡萄糖醛酸。它参与表阿霉素解毒和透明质酸合成。本工作旨在评估 UGDH 敲低对 MDA-MB-231 乳腺癌细胞中表阿霉素反应和透明质酸代谢的影响。此外,还旨在确定 UGDH 是否可作为乳腺癌的预后标志物。我们研究了乳腺癌患者肿瘤和相邻组织中的 UGDH 表达。使用公共 Kaplan-Meier 绘图仪研究了 UGDH 的预后价值。MDA-MB-231 细胞敲低 UGDH 并接受表阿霉素治疗。通过流式细胞术分析表阿霉素蓄积和细胞凋亡。通过 Western blot 和共聚焦显微镜研究自噬 LC3-II。UGDH 敲低后,表阿霉素蓄积增加,细胞凋亡减少。透明质酸涂层基质增加,并检测到自噬的正调控。在接受化疗的三阴性乳腺癌患者中,UGDH 水平较高与预后较差相关。在 HER2 患者的肿瘤组织中发现 UGDH 高表达。然而,UGDH 敲低导致表阿霉素耐药,这可能与透明质酸的表达、沉积和分解代谢增加有关。研究结果表明,UGDH 可作为乳腺癌的新预后标志物,与表阿霉素耐药的发展和细胞外基质的调节呈正相关。