Dong Lu, Liu Sifan, Sun Wenjing, Liu Siying, Zhang Nan, Zhang Shutian
School of Clinical Medicine, Shandong Second Medical University, Weifang, 261000, China.
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory for Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, 100050, China.
Curr Cancer Drug Targets. 2025;25(3):306-316. doi: 10.2174/0115680096337375240801080008.
The purpose of this study was to investigate the role of DGUOK in the progression of colorectal cancer (CRC) and its impact on the sensitivity of CRC cells to 5-FU treatment.
We conducted bioinformatics analysis and qRT-PCR to evaluate DGUOK expression in CRC tissues/cells. Cell viability of CRC cells treated with 5-FU was assessed using CCK-8 and colony formation assays. Autophagy levels were determined through immunofluorescence assays and Western blot analysis. Additionally, the influence of p-p38 on autophagy was investigated Western blotting. A rescue assay was performed to confirm whether DGUOK/p38 affects 5-FU sensitivity in CRC cells through autophagy.
Our findings indicate that DGUOK is upregulated in CRC tissues compared to normal tissues, correlating with increased cell proliferation and migration. Functionally, inhibition of DGUOK enhances autophagy, thereby decreasing the sensitivity of CRC cells to 5-FU. This effect is partly mediated by DGUOK's impact on the mitogen-activated protein kinase (MAPK) pathway, specifically promoting the phosphorylation of p38 MAPK, a crucial regulator in autophagy pathways.
These results suggest that DGUOK could serve as a novel marker for predicting the efficacy of 5-FU in CRC treatment.
本研究旨在探讨二氢尿嘧啶脱氢酶（DGUOK）在结直肠癌（CRC）进展中的作用及其对CRC细胞对5-氟尿嘧啶（5-FU）治疗敏感性的影响。
我们进行了生物信息学分析和定量逆转录聚合酶链反应（qRT-PCR）以评估DGUOK在CRC组织/细胞中的表达。使用细胞计数试剂盒-8（CCK-8）和集落形成试验评估用5-FU处理的CRC细胞的活力。通过免疫荧光试验和蛋白质印迹分析确定自噬水平。此外，通过蛋白质印迹研究磷酸化p38对自噬的影响。进行了拯救试验以确认DGUOK/p38是否通过自噬影响CRC细胞对5-FU的敏感性。
我们的研究结果表明，与正常组织相比，DGUOK在CRC组织中上调，这与细胞增殖和迁移增加相关。在功能上，抑制DGUOK可增强自噬，从而降低CRC细胞对5-FU的敏感性。这种作用部分是由DGUOK对丝裂原活化蛋白激酶（MAPK）途径的影响介导的，特别是促进p38丝裂原活化蛋白激酶（p38 MAPK）的磷酸化，p38 MAPK是自噬途径中的关键调节因子。
这些结果表明，DGUOK可作为预测5-FU在CRC治疗中疗效的新标志物。
