Serum mitochondrial tsRNA serves as a novel biomarker for hepatocarcinoma diagnosis

doi:10.1007/s11684-022-0920-7

Front. Med.

2022, Vol. 16

Issue (2) : 216-226 https://doi.org/10.1007/s11684-022-0920-7

RESEARCH ARTICLE

Serum mitochondrial tsRNA serves as a novel biomarker for hepatocarcinoma diagnosis

Shoubin Zhan¹, Ping Yang², Shengkai Zhou¹, Ye Xu¹, Rui Xu¹, Gaoli Liang¹, Chenyu Zhang¹, Xi Chen¹, Liuqing Yang⁴(

), Fangfang Jin³(

), Yanbo Wang¹(

)

¹. Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology and Department of Physiology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing 210023, China
². Department of Clinical Laboratory, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210023, China
³. School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
⁴. Department of Infectious Diseases, The First People’s Hospital of Lianyungang, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang 222000, China

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Abstract

Hepatocellular carcinoma (HCC), which makes up the majority of liver cancer, is induced by the infection of hepatitis B/C virus. Biomarkers are needed to facilitate the early detection of HCC, which is often diagnosed too late for effective therapy. The tRNA-derived small RNAs (tsRNAs) play vital roles in tumorigenesis and are stable in circulation. However, the diagnostic values and biological functions of circulating tsRNAs, especially for HCC, are still unknown. In this study, we first utilized RNA sequencing followed by quantitative reverse-transcription PCR to analyze tsRNA signatures in HCC serum. We identified tRF-Gln-TTG-006, which was remarkably upregulated in HCC serum (training cohort: 24 HCC patients vs. 24 healthy controls). In the validation stage, we found that tRF-Gln-TTG-006 signature could distinguish HCC cases from healthy subjects with high sensitivity (80.4%) and specificity (79.4%) even in the early stage (Stage I: sensitivity, 79.0%; specificity, 74.8%; 155 healthy controls vs. 153 HCC patients from two cohorts). Moreover, in vitro studies indicated that circulating tRF-Gln-TTG-006 was released from tumor cells, and its biological function was predicted by bioinformatics assay and validated by colony formation and apoptosis assays. In summary, our study demonstrated that serum tsRNA signature may serve as a novel biomarker of HCC.

Keywords tsRNA biomarker hepatocarcinoma

Corresponding Author(s): Liuqing Yang,Fangfang Jin,Yanbo Wang

About author:

Mingsheng Sun and Mingxiao Yang contributed equally to this work.

Just Accepted Date: 25 February 2022 Online First Date: 11 April 2022 Issue Date: 26 April 2022

Cite this article:

Shoubin Zhan,Ping Yang,Shengkai Zhou, et al. Serum mitochondrial tsRNA serves as a novel biomarker for hepatocarcinoma diagnosis[J]. Front. Med., 2022, 16(2): 216-226.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0920-7
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I2/216

Tab.1 Information of the HCC patients of the two hospitals cohorts

Fig.1 Flowchart of the study design.

Fig.2 Analysis of differentially expressed serum tsRNAs in HCC. (A) The scatter plot expressed the changes in tsRNAs expression. (B) Heat map of 17 significant differentially expressed tsRNAs. (C−G) qRT-PCR data on the tsRNA expression levels in the screen phases (n_HCC = 24, n_control = 24) of tRF-Val-CAC-010 (C), tRF-Pro-AGG-005 (D), tRF-Gln-TTG-006 (E), tRF-His-GTG-009 (F), and tRF-Ser-GCT-024 (G). **P < 0.01; **** P < 0.0001.

Fig.3 Training phase of tRF-Gln-TTG-006 in the two cohorts from different hospitals. (A and B) qRT-PCR shows the concentrations of tRF-Gln-TTG-006 in serum from The First People’s Hospital of Lianyungang (cohort 1) (A) and The Affiliated Drum Tower Hospital of Nanjing University Medical School (cohort 2) (B). (C–E) ROC curves analysis compared the diagnosis value of tRF-Gln-TTG-006 and AFP concentration in serum in the cohort 1 (green line, AUC = 0.919) (C), cohort 2 (green line, AUC = 0.825) (D), cohort 1 + 2 (blue line, AUC = 0.875; gray line AUC = 0.737) (E). (F) ROC curves of tRF-Gln-TTG-006 and AFP concentration in serum from clinical stage I cases and controls in all sets (orange line, AUC = 0.858; gray line, AUC = 0.710). ****P < 0.0001.

Fig.4 Biological functions of tRF-Gln-TTG-006. (A) Quantitative analysis of tRF-Gln-TTG-006 expression in HCC tissues and paired serum from same patients (n = 11). (B) Expression status of tRF-Gln-TTG-006 in HepG2 cell culture medium. The amount of tRF-Gln-TTG-006 excreted in the culture medium increased depending on the cell number. (C) Position of tRF-Gln-TTG-006 in the cloverleaf secondary structure of trnaMT_GlnTTG_MT_-_4329_4400. (D) Colony formation assay was performed on HuH-7 and HepG2 cells transfected with mimic nc or tRF-Gln-TTG-006 mimic. (E and F) Quantitative analysis of the colony number of HuH-7 (E) and HepG2 cells (F). (G and H) tRF-Gln-TTG-006 inhibited apoptosis in HuH-7 cells (G) and quantitative analysis of apoptosis (H). *P < 0.05; ** P < 0.01.

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