5′-tiRNA-Gln inhibits hepatocellular carcinoma progression by repressing translation through the interaction with eukaryotic initiation factor 4A-I  

作　　者：Chengdong Wu Dekai Liu Lufei Zhang Jingjie Wang Yuan Ding Zhongquan Sun Weilin Wang 

机构地区：[1]Department of Hepatobiliary and Pancreatic Surgery,The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China [2]Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province,Hangzhou 310009,China [3]Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province,Hangzhou 310009,China [4]Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University,Hangzhou 310009,China [5]Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province,Hangzhou 310009,China [6]Cancer Center,Zhejiang University,Hangzhou 310009,China

出　　处：《Frontiers of Medicine》2023年第3期476-492,共17页医学前沿（英文版）

基　　金：generously supported by the National Natural Science Foundation of China(Nos.82072650 and 81902405);Key Research and Development Program of Zhejiang Province(No.2021C03121);2019 Liver Cancer Diagnosis and Treatment Communication Fund(No.CXPJJH11900009-12);Grant from Health Commission of Zhejiang Province(No.JBZX-202004).

摘　　要：tRNA-derived small RNAs(tsRNAs)are novel non-coding RNAs that are involved in the occurrence and progression of diverse diseases.However,their exact presence and function in hepatocellular carcinoma(HCC)remain unclear.Here,differentially expressed tsRNAs in HCC were profiled.A novel tsRNA,tRNAGln-TTG derived 5′-tiRNA-Gln,is significantly downregulated,and its expression level is correlated with progression in patients.In HCC cells,5′-tiRNA-Gln overexpression impaired the proliferation,migration,and invasion in vitro and in vivo,while 5′-tiRNA-Gln knockdown yielded opposite results.5′-tiRNA-Gln exerted its function by binding eukaryotic initiation factor 4A-I(EIF4A1),which unwinds complex RNA secondary structures during translation initiation,causing the partial inhibition of translation.The suppressed downregulated proteins include ARAF,MEK1/2 and STAT3,causing the impaired signaling pathway related to HCC progression.Furthermore,based on the construction of a mutant 5′-tiRNA-Gln,the sequence of forming intramolecular G-quadruplex structure is crucial for 5′-tiRNA-Gln to strongly bind EIF4A1 and repress translation.Clinically,5′-tiRNA-Gln expression level is negatively correlated with ARAF,MEK1/2,and STAT3 in HCC tissues.Collectively,these findings reveal that 5′-tiRNA-Gln interacts with EIF4A1 to reduce related mRNA binding through the intramolecular Gquadruplex structure,and this process partially inhibits translation and HCC progression.

关 键 词：EIF4A1 G-QUADRUPLEX hepatocellular carcinoma tRNA-derived small RNA translation initiation 

分 类 号：R735.7[医药卫生—肿瘤]