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

doi:10.1007/s11684-022-0966-6

Front. Med.

2023, Vol. 17

Issue (3) : 476-492 https://doi.org/10.1007/s11684-022-0966-6

RESEARCH ARTICLE

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

Chengdong Wu, Dekai Liu, Lufei Zhang, Jingjie Wang, Yuan Ding, Zhongquan Sun, Weilin Wang(

)

Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China; Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou 310009, China; Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China; Cancer Center, Zhejiang University, Hangzhou 310009, China

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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

Corresponding Author(s): Weilin Wang

Just Accepted Date: 21 February 2023 Online First Date: 27 March 2023 Issue Date: 28 July 2023

Cite this article:

Chengdong Wu,Dekai Liu,Lufei Zhang, et al. 5′-tiRNA-Gln inhibits hepatocellular carcinoma progression by repressing translation through the interaction with eukaryotic initiation factor 4A-I[J]. Front. Med., 2023, 17(3): 476-492.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0966-6
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I3/476

Tab.1 Clinical characteristics of 76 HCC patients

Fig.1 Profiles of small ncRNAs in HCC tissues. (A) tiRNA levels of four paired HCC (T) and adjacent non-tumorous tissues (A). (B) Read length distribution in the tumor (cancer) and adjacent (normal) tissue groups. The bar chart shows the total counts against the lengths of the trimmed reads. (C) Aligned percentage of miRNAs, mature (Mat)-tRNA- and precursor (Pre)-tRNA-derived small ncRNAs from the tumor and adjacent tissue groups. (D) Venn diagram based on the number of commonly and specifically expressed tsRNAs. Blue, tumor group; red, adjacent tissue group. (E) Schematic of tsRNA subtypes. (F) Distribution profiles of the tsRNA subtypes in the tumor and adjacent tissue groups.

Fig.2 5′-tiRNA-Gln is downregulated in HCC tissue and associated with HCC progression. (A) Volcano plot of differentially expressed tsRNAs in the tumor group compared with that in the adjacent tissues group. Red: upregulated; green: downregulated. (B) Heatmap showing the differentially expressed tiRNAs in HCC (including 5′-tiRNAs and 3′-tiRNAs). (C) 5′-tiRNA-Gln expression in 76 paired HCC and adjacent non-tumorous tissue samples. Chart below: Paired comparison of 5′-tiRNA-Gln expression levels between the tumor and adjacent tissues (tumor/adjacent). (D) Northern blot detection of 5′-tiRNA-Gln expression in tumor and adjacent tissues. (E, F) Mean 5′-tiRNA-Gln levels in HCC tissues with or without metastasis (E) and tumor size < 5 cm or ≥ 5 cm (F). *P < 0.05, ***P < 0.001.

Fig.3 5′-tiRNA-Gln inhibited HCC cell proliferation, migration, and invasion in vitro and in vivo. (A) CCK-8 assay detection of Huh-7 cell viability after transfection of 5′-tiRNA-Gln or control RNA. (B) Representative images and quantification of Transwell migration and invasion assays of the transfected Huh-7 cells (scale bar: 100 μm). (C) CCK-8 assay detection of SK-Hep-1 cell viability after the transfection of siRNA targeting 5′-tiRNA-Gln (Si 5′-tiRNA-Gln) or control siRNA (Si Control). (D) Representative images and quantification of Transwell migration and invasion assays of the transfected SK-Hep-1 cells (scale bar: 100 μm). (E) Tumor images (left) and weights (right) of xenograft tumors formed 6 weeks after subcutaneous injection of Huh-7 cells stably transfected with 5′-tiRNA-Gln or control RNA into nude mice (n = 5 per group). (F) Colony formation assay of Huh-7 cells stably expressing 5′-tiRNA-Gln (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001.

Fig.4 5′-tiRNA-Gln interacted selectively with EIF4A1. (A) Left: Venn diagram based on the number of proteins commonly and specifically pulled down by 5′-tiRNA-Gln or control RNA. Right: Top 10 scores of proteins specifically pulled down by 5′-tiRNA-Gln. (B) Overall survival analysis of patients with HCC according to the EIF4A1 expression levels (n = 91 per group). Significance was estimated using log-rank test. (C) Western blot analysis of EIF4A1 pulled down by biotin-labeled 5′-tiRNA-Gln or control RNA in Huh-7 cells. (D) RIP assay of 5′-tiRNA-Gln levels in EIF4A1 immunoprecipitate detected by DNA electrophoresis. IgG was the negative control. (E) Immunofluorescence experiments showing that 5′-tiRNA-Gln and EIF4A1 colocalized in the cytoplasm of Huh-7 cells. Blue, DAPI-stained nuclei; yellow, EIF4A1; red, 5′-tiRNA-Gln (scale bar: 20 μm).

Fig.5 5′-tiRNA-Gln repressed translation in Huh-7 cells. (A) Puromycin capture assay showing that 5′-tiRNA-Gln reduced nascent protein synthesis. (B) Volcano plot of differentially expressed proteins in the 5′-tiRNA-Gln overexpression group as compared with the control group. Red: upregulated; green: downregulated. (C) COG analysis of the downregulated proteins showing the most enriched terms. Red, cellular processes and signaling; blue, information storage and processing; green, metabolism. (D) KEGG pathway analysis of the downregulated proteins showed that the 15 related pathways changed significantly in Huh-7 cells. (E) Western blot analysis detection of the quantity of ARAF, MEK1/2, p-ERK1/2, STAT3, p-STAT3, and BID.

Fig.6 Mutant 5′-tiRNA-Gln lost the function of inhibiting Huh-7 cell viability. (A) CCK-8 assay detection of Huh-7 cells viability. Red, transfected with control RNA; green, mutant 5′-tiRNA-Gln; blue, 5′-tiRNA-Gln. (B) Representative images and quantification of Transwell migration and invasion assays of Huh-7 cells. (C) RNA pull-down assay showing that mutant 5′-tiRNA-Gln failed to bind with EIF4A1 compared with 5′-tiRNA-Gln (scale bar: 100 μm). (D) Polysome profiling showing the reduction of mRNA binding polysomes in Huh-7 cells transfected with 5′-tiRNA-Gln. (E) Cytoplasmic mRNA levels of ARAF, MEK1, MEK2, and STAT3 in Huh-7 cells, n.s. (no significance). (F) mRNA enrichment in EIF4A1 immunoprecipitates. The mRNA levels were normalized to that of the control group. IgG was the negative control. (G) Western blot analysis results show that 5′-tiRNA-Gln transfection downregulated the quantity of ARAF, MEK1/2, p-ERK1/2, STAT3, and p-STAT3. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig.7 5′-tiRNA-Gln is negatively correlated with ARAF, MEK1/2, and STAT3 expression in HCC tissues. (A) Representative IHC staining images of tumors in a tissue microarray containing 51 pairs of HCC and adjacent non-tumorous tissues (scale bar: 100 μm). Relationship between 5′-tiRNA-Gln and ARAF, MEK1/2, or STAT3 was assessed with Spearman’s correlation analysis. (B) Schematic diagram of the role of 5′-tiRNA-Gln in HCC progression.

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