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 t...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.展开更多
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)+1 种基金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).
文摘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.
