Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jun 15, 2023; 15(6): 1005-1018
Published online Jun 15, 2023. doi: 10.4251/wjgo.v15.i6.1005
5’tiRNA-Pro-TGG, a novel tRNA halve, promotes oncogenesis in sessile serrated lesions and serrated pathway of colorectal cancer
Xin-Yuan Wang, Yu-Jie Zhou, Hai-Ying Chen, Jin-Nan Chen, Shan-Shan Chen, Hui-Min Chen, Xiao-Bo Li
Xin-Yuan Wang, Yu-Jie Zhou, Hai-Ying Chen, Jin-Nan Chen, Hui-Min Chen, Xiao-Bo Li, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
Shan-Shan Chen, Department of Spleen and Stomach and Rheumatology, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
Author contributions: Li XB was the guarantor of the paper; Wang XY and Chen SS collected clinical samples and performed the experiments; Chen HY analyzed data; Wang XY and Zhou YJ wrote the original draft; Chen JN revised the manuscript; Li XB and Chen HM conceived and supervised the study; All the authors revised and approved the final manuscript.
Supported by the Program of Health and Family Planning Research Project Plan of Pudong New Area Health Committee, No. PW2020D-12.
Institutional review board statement: This study was approved by Shanghai Jiaotong University School of Medicine, Renji Hospital Ethics Committee, No. KY2021-004.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao-Bo Li, PhD, Chief Doctor, Chief Physician, Professor, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, No. 145 Middle Shandong Road, Shanghai 200000, China. lxb_1969@163.com
Received: February 1, 2023
Peer-review started: February 1, 2023
First decision: February 16, 2023
Revised: February 27, 2023
Accepted: April 17, 2023
Article in press: April 17, 2023
Published online: June 15, 2023
Processing time: 133 Days and 18.5 Hours
Abstract
BACKGROUND

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are small fragments that form when tRNAs severe. tRNA halves (tiRNAs), a subcategory of tsRNA, are involved in the oncogenic processes of many tumors. However, their specific role in sessile serrated lesions (SSLs), a precancerous lesion often observed in the colon, has not yet been elucidated.

AIM

To identify SSL-related tiRNAs and their potential role in the development of SSLs and serrated pathway of colorectal cancer (CRC).

METHODS

Small-RNA sequencing was conducted in paired SSLs and their adjacent normal control (NC) tissues. The expression levels of five SSL-related tiRNAs were validated by q-polymerase chain reaction. Cell counting kit-8 and wound healing assays were performed to detect cell proliferation and migration. The target genes and sites of tiRNA-1:33-Pro-TGG-1 (5′tiRNA-Pro-TGG) were predicted by TargetScan and miRanda algorithms. Metabolism-associated and immune-related pathways were analyzed by single-sample gene set enrichment analysis. Functional analyses were performed to establish the roles of 5′tiRNA-Pro-TGG based on the target genes.

RESULTS

In total, we found 52 upregulated tsRNAs and 28 downregulated tsRNAs in SSLs compared to NC. The expression levels of tiRNA-1:33-Gly-CCC-2, tiRNA-1:33-Pro-TGG-1, and tiRNA-1:34-Thr-TGT-4-M2 5′tiRNAs were higher in SSLs than those in NC, while that of 5′tiRNA-Pro-TGG was associated with the size of SSLs. It was demonstrated that 5′tiRNA-Pro-TGG promoted cell proliferation and migration of RKO cell in vitro. Then, heparanase 2 (HPSE2) was identified as a potential target gene of 5′tiRNA-Pro-TGG. Its lower expression was associated with a worse prognosis in CRC. Further, lower expression of HPSE2 was observed in SSLs compared to normal controls or conventional adenomas and in BRAF-mutant CRC compared to BRAF-wild CRC. Bioinformatics analyses revealed that its low expression was associated with a low interferon γ response and also with many metabolic pathways such as riboflavin, retinol, and cytochrome p450 drug metabolism pathways.

CONCLUSION

tiRNAs may profoundly impact the development of SSLs. 5′tiRNA-Pro-TGG potentially promotes the progression of serrated pathway CRC through metabolic and immune pathways by interacting with HPSE2 and regulating its expression in SSLs and BRAF-mutant CRC. In the future, it may be possible to use tiRNAs as novel biomarkers for early diagnosis of SSLs and as potential therapeutic targets in serrated pathway of CRC.

Keywords: Noncoding RNA; tRNA halves; Sessile serrated lesions; Colon cancer; Serrated pathway

Core Tip: Our study identified the transfer RNA-derived small RNAs expression profile of sessile serrated lesions (SSLs) for the first time and found that tRNA halves (tiRNAs)-1:33-Pro-TGG-1, which was associated with polyp size, were highly expressed in SSLs and promoted oncogenesis in colorectal cancer cell. Furthermore, tiRNA-1:33-Pro-TGG-1 potentially promotes the progression of serrated pathway colorectal cancer (CRC) through metabolic and immune pathways by interacting with HPSE2 in SSLs and BRAF mutant CRC. In the future, tiRNA-1:33-Pro-TGG-1 may serve as a potential target for the early diagnosis of SSLs and treatment of CRC that arises from the serrated pathway.