5'tiRNA-Pro-TGG, a novel tRNA halve, promotes oncogenesis in sessile serrated lesions and serrated pathway of colorectal cancer

• Published in: World journal of gastrointestinal oncology 2023-06, Vol.15 (6), p.1005-1018
• Main Authors: Wang, Xin-Yuan, Zhou, Yu-Jie, Chen, Hai-Ying, Chen, Jin-Nan, Chen, Shan-Shan, Chen, Hui-Min, Li, Xiao-Bo
• Format: Article
• Language: English
• Subjects: Basic Study
• ISSN: 1948-5204; 1948-5204
• DOI: 10.4251/wjgo.v15.i6.1005

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. To identify SSL-related tiRNAs and their potential role in the development of SSLs and serrated pathway of colorectal cancer (CRC). 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. 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 . Then, heparanase 2 ( ) 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 was observed in SSLs compared to normal controls or conventional adenomas and in -mutant CRC compared to -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. 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 and regulating its expression in SSLs and -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.