Published online Jun 15, 2023. doi: 10.4251/wjgo.v15.i6.1005
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
tRNA halves (tiRNAs), a subcategory of tRNA-derived small RNAs (tsRNA), are involved in the oncogenic processes of many tumors, yet their specific role in sessile serrated lesions (SSLs) has not yet been elucidated.
The motivation for this study is to identify SSL-related tiRNAs and their potential role in the development of SSLs and serrated pathways in colorectal cancer (CRC).
Endoscopic detection of SSLs is very difficult and we do not know much about the exact mechanisms through which SSLs develop and how they progress to CRC in present.
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 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.
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 NC or 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.
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 5′tiRNA-Pro-TGG as a novel biomarker for early diagnosis of SSLs and as a potential therapeutic target in serrated pathway of CRC.