Ribonucleotide reductase small subunit M2 promotes the proliferation of esophageal squamous cell carcinoma cells via HuR-mediated mRNA stabilization  

作　　者：Jing Zhang Qiong Wu Yifei Xie Feng Li Huifang Wei Yanan Jiang Yan Qiao Yinhua Li Yanan Sun Han Huang Mengmeng Ge Dengyun Zhao Zigang Dong Kangdong Liu 

机构地区：[1]Pathophysiology Department,School of Basic Medical Sciences,Zhengzhou University,Zhengzhou 450000,China [2]China-US(Henan)Hormel Cancer Institute,Zhengzhou 450000,China [3]Tianjian Laboratory for Advanced Biomedical Sciences,Zhengzhou 450052,China [4]State Key Laboratory of Esophageal Cancer Prevention and Treatment,Zhengzhou 450000,China [5]Cancer Chemoprevention International Collaboration Laboratory,Zhengzhou 450000,China [6]The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450000,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第10期4329-4344,共16页药学学报（英文版）

基　　金：funded by National Natural Science Foundation of China(grant numbers:81872335,82303891 and 82303119);The Central Plains Science and Technology Innovation Leading Talents(No.224200510015,China);Key scientific research project plan of colleges and universities in Henan Province(grant number:24A310025,China);Science and Technology Project of Henan Province(No.242102310414,China).

摘　　要：Esophageal squamous cell carcinoma(ESCC),a malignancy of the digestive system,is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets.Dysregulated ribonucleotide reductase(RNR)expression has been confirmed to be causally linked to tumorigenesis.This study demonstrated that ribonucleotide reductase small subunit M2(RRM2)is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes.Mechanistically,HuR promotes RRM2 mRNA stabilization by binding to the adenine/uridine(AU)-rich elements(AREs)within the 3′UTR,resulting in persistent overexpression of RRM2.Furthermore,bifonazole is identified as an inhibitor of HuR via computational screening and molecular docking analysis.Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65,R97,I103,and R153 residues,resulting in reduced RRM2 expression.Furthermore,bifonazole exhibited antitumor effects on ESCC patient-derived xenograft(PDX)models by decreasing RRM2 expression and the dNTP pool.In summary,this study reveals the interaction network among HuR,RRM2,and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.

关 键 词：Esophageal squamous cell carcinoma(ESCC) Bifonazole Ribonucleotide reductase small subunit M2(RRM2) AU-rich elements(AREs) Hu antigen R(HuR) mRNA stability DNTP Cell proliferation 

分 类 号：R735.1[医药卫生—肿瘤]