The mechanism of YB1-mediated MDR1 regulation in cisplatin-induced drug resistance of intrahepatic cholangiocarcinoma
10.19405/j.cnki.issn1000-1492.2026.08.007
- VernacularTitle:YB1介导MDR1调控肝内胆管细胞癌顺铂诱导耐药机制研究
- Author:
Siqi WANG
1
;
Miao CHEN
2
;
Xinyu LUO
3
;
Heng LIU
1
Author Information
1. Department of Gastroenterology， The First Affiliated Hospital of Anhui Medical University， Hefei 230022
2. The First Clinical College of Anhui Medical University， Hefei 230022
3. The Second Clinical College of Anhui Medical University， Hefei 230601
- Publication Type:Journal Article
- Keywords:
Y-box binding protein 1;
multidrug resistance gene 1;
intrahepatic cholangiocarcinoma;
cisplatin;
chemotherapy resistance;
methylation
- From:
Acta Universitatis Medicinalis Anhui
2026;61(8):1383-1391
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo explore the mechanism by which Y-box binding protein 1 （YB1） mediates the expression of multidrug resistance gene 1 （MDR1） and regulates cisplatin-induced resistance in intrahepatic cholangiocarcinoma （ICC）. MethodsAfter treating human ICC HCCC-9810 cells with different concentrations of cisplatin， Western blot and immunofluorescence techniques were used to detect the expression of YB1 and phosphorylated YB1 （pYB1） and changes in their cellular localization. In addition， qPCR and Western blot were used to analyze the expression changes of drug resistance-related proteins MDR1， multidrug resistance-associated protein 2 （MRP2）， and major vault protein （MVP）. Chromatin immunoprecipitation （ChIP） assay was performed to examine the binding of YB1 to the MDR1 promoter in HCCC-9810 cells with or without cisplatin treatment. Additionally， bisulfite sequencing （BS-seq） was used to determine the methylation status of cytosine-phosphate-guanine （CpG） islands within the MDR1 promoter in HCCC-9810 cells， before and after cisplatin treatment. ResultsAfter HCCC-9810 cells were treated with cisplatin， the total amount of intracellular YB1 protein did not change， but the level of pYB1 gradually increased， accompanied by the nuclear migration of YB1 and pYB1 protein. After HCCC-9810 cells were induced with cisplatin， the expression of MDR1 significantly increased， and the drug resistance of the cells also increased. If the expression of MDR1 was inhibited beforehand， the increase in drug resistance of the cells can be reversed. Similarly， after knocking down the expression of YB1 in HCCC-9810 cells， the nuclear migration of YB1 and pYB1 significantly decreased， and the expression of MDR1 significantly decreased， resulting in a significant increase in sensitivity to cisplatin chemotherapy. When HCCC-9810 cells were not stimulated by external factors， the CpG island in the promoter region of MDR1 showed a high methylation state， and multiple transcription factors， including YB1， could not bind to it. When HCCC-9810 cells were treated with cisplatin， the CpG island in the promoter region of MDR1 underwent demethylation， and the binding force between YB1 and the MDR1 promoter in the nucleus increased， activating MDR1 expression. ConclusionYB1 is highly expressed in the cytoplasm of ICC cells. Cisplatin chemotherapy induces nuclear translocation of YB1， accompanied by demethylation of the CpG island in the MDR1 promoter. Nuclear YB1 binds to the MDR1 promoter and activates transcription， ultimately leading to chemotherapy resistance.
