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

Abstract

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, tRNA^Gln-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 G-quadruplex structure, and this process partially inhibits translation and HCC progression.

Keywords

EIF4A1 / G-quadruplex / hepatocellular carcinoma / tRNA-derived small RNA / translation initiation

Chengdong Wu et al.

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Acknowledgements

This work was 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) and Grant from Health Commission of Zhejiang Province (No. JBZX-202004).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0966-6 and is accessible for authorized users.

Compliance with ethics guidelines

Chengdong Wu, Dekai Liu, Lufei Zhang, Jingjie Wang, Yuan Ding, Zhongquan Sun, and Weilin Wang declare that they have no conflicts of interest. All the procedure of the study was approved by Internal Review and Ethic Boards at the Second Affiliated Hospital of Zhejiang University School of Medicine. All institutional and national guidelines for the care and use of laboratory animals were followed.

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