南方医科大学学报2026，Vol.46Issue(5)：1066-1074,9.DOI:10.12122/j.issn.1673-4254.2026.05.10
乙醇通过激活TGF-β/Smad/P21信号轴促进结直肠癌奥沙利铂的耐药性
Ethanol promotes oxaliplatin resistance in colorectal cancer by activating the TGF-β/Smad/P21 signaling axis
摘要
Abstract
Objective To investigate the effect of ethanol for promoting oxaliplatin resistance in colorectal cancer(CRC)and the underlying molecular mechanisms.Methods Lifetime alcohol consumption data from the PLCO cohort were analyzed to assess the association between alcohol drinking and CRC risk.The differential expressions of alcohol metabolism-related genes between CRC and normal tissues and their associations with recurrence and survival in chemotherapy-treated patients were analyzed based on GEO datasets.Fecal samples from healthy non-drinkers and CRC patients were collected for detecting ethanol levels using gas chromatography-mass spectrometry(GC-MS).In a mouse model bearing subcutaneous CRC xenograft treated with oxaliplatin,the effects of continuous ethanol exposure using the Lieber-DeCarli liquid diet and 4-methylpyrazole(4-MP)treatment on tumor growth were evaluated.In cultured SW480 and HCT116 cells,the effect of 100 and 200 mg/dL ethanol on oxaliplatin sensitivity,apoptosis,cell cycle distribution,and TGF-β/Smad/P21/Rb axis proteins were analyzed,and the results were further validated with pirfenidone intervention experiment.Results High-frequency drinkers had a significantly increased risk of CRC.ADH1B and ADH1C were significantly downregulated in CRC tissues,and their low expressions were associated with a higher recurrence rate and poorer overall survival in chemotherapy-treated patients.Ethanol was detected in fecal samples from both healthy individuals and CRC patients.In oxaliplatin-treated tumor-bearing mice,alcohol exposure resulted in a greater tumor volume.In SW480 and HCT116 cells,ethanol significantly increased oxaliplatin IC₅₀,reduced cell apoptosis,induced G0/G1 arrest,decreased S-phase fraction,and upregulated TGF-β1,p-Smad2,and P21 while downregulating p-Rb expression.Pirfenidone partially reversed these changes and attenuated drug resistance of the cells.Conclusion Ethanol accumulation activates the TGF-β/Smad/P21 axis to induce cell cycle arrest and promote oxaliplatin resistance in CRC cells,which can be partially reversed by pirfenidone inhibition.关键词
乙醇/结直肠癌/奥沙利铂耐药/TGF-β/Smad/P21/吡非尼酮Key words
ethanol/colorectal cancer/oxaliplatin resistance/TGF-β/Smad/P21/pirfenidone引用本文复制引用
谭彬,翁诺舟,曾文涛,古家宇,翁炼基,温慧琳,肖浩成,郑克鸿..乙醇通过激活TGF-β/Smad/P21信号轴促进结直肠癌奥沙利铂的耐药性[J].南方医科大学学报,2026,46(5):1066-1074,9.基金项目
国家自然科学基金青年项目(82103399) （82103399）
广州市基础研究计划项目(2024A04J9992)Supported by Natural Science Foundation for the Youth(NSFY)of China(82103399). （2024A04J9992）
