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Wu Y, Li H, Long Y, Zhang Z, Zhang F, Pan R, Meng L, Ma Z, Wang K, Zheng B, Qie Z, Gao W. Epigenetic Suppression of miR-137 Induces RNF4 Expression, Facilitating Wnt Signaling in Colorectal Cancer. Mol Carcinog 2025; 64:475-489. [PMID: 39630054 DOI: 10.1002/mc.23859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/01/2024] [Accepted: 11/15/2024] [Indexed: 01/05/2025]
Abstract
Colorectal cancer (CRC) is a significant health issue worldwide. Recent studies highlight the critical role of miRNAs in CRC development, particularly miR-137, which acts as a key tumor suppressor. Despite its known role, further exploration of miR-137's downstream signaling is needed to understand its biology and therapeutic potential. We examined the methylation status of miR-137 using one TCGA data and three GEO data sets. A clinical validation cohort of 78 samples was analyzed using MSP for miR-137 promoter methylation. Various in vitro molecular/cellular and animal experiments were conducted to elucidate miR-137's role in CRC. Bioinformatic analysis indicated frequent methylation of miR-137 in CRC tissues, correlating with suppressed expression. EZH2-mediated H3K27 trimethylation silences miR-137 in CRC cells by increasing chromatin compaction, reversible by EZH2 siRNA or inhibitor GSK343. miR-137 inhibits CRC cell proliferation, migration, invasion, and xenograft tumor growth, confirming its tumor-suppressive role. Using the miRWalk repository showed that miR-137 regulates the Wnt signaling pathway by reducing typical protein expression in HCT116 and SW480 cells. miR-137 directly targets RNF4, leading to its downregulation at transcriptional and protein levels, with an observed inverse correlation in CRC tissues. miR-137 accelerates c-Myc and β-catenin degradation by inhibiting RNF4, impacting protein stability and Wnt pathway inhibition. miR-137 is epigenetically silenced through DNA methylation and EZH2-mediated H3K27 trimethylation. It regulates the Wnt signaling pathway by targeting RNF4, leading to c-Myc and β-catenin destabilization. Restoring miR-137 or inhibiting RNF4 suppresses CRC cell proliferation, migration, invasion, and tumor growth, highlighting its therapeutic potential in CRC.
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Affiliation(s)
- Yazhou Wu
- Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Department of Laboratory Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Clinical Laboratory, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hanhua Li
- Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Clinical Laboratory, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yin Long
- Department of Clinical Laboratory, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenzhen Zhang
- Department of Clinical Laboratory, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Fanping Zhang
- Department of Clinical Laboratory, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Runyu Pan
- Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Leijun Meng
- Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhan Ma
- Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kaijing Wang
- Department of Hepatobiliary Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bing Zheng
- Department of Laboratory Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhonghong Qie
- Department of Clinical Laboratory, Shanghai health and medical center, Wuxi, China
| | - Wei Gao
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Li H, Zhang L, Li ML, Chen ZF, Fei SK. Progress in application and research of tsRNAs in digestive system tumors. Shijie Huaren Xiaohua Zazhi 2024; 32:872-877. [DOI: 10.11569/wcjd.v32.i12.872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/04/2024] [Accepted: 10/30/2024] [Indexed: 12/28/2024] Open
Abstract
Transfer RNA-derived small RNAs (tsRNAs) are a class of non-coding small RNAs derived from mature transfer RNAs or transfer RNA precursors under specific conditions, and they exhibit abnormal expression in various digestive system tumors. In recent years, research has revealed that abnormal expression of tsRNAs can not only serve as biomarkers for the early diagnosis of digestive system tumors but also play significant regulatory roles in the proliferation, invasion, and metastasis of digestive system tumor cells. tsRNAs provide a novel group of biomarkers for early diagnosis and new therapeutic directions for patients with digestive system tumors. This article reviews the progress in application and research of tsRNAs in common digestive system tumors such as gastric cancer, liver cancer, and colorectal cancer, providing new directions for their clinical diagnosis and treatment.
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Affiliation(s)
- Hui Li
- Department of Hepatobiliary, Pancreatic, and Splenic Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Liang Zhang
- Department of Nephrology, Rheumatology, and Immunology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Ming-Liang Li
- Department of Hepatobiliary, Pancreatic, and Splenic Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Zhi-Fei Chen
- Department of General Surgery, The Third Hospital of Changsha, Changsha 410000, Hunan Province, China
| | - Shu-Ke Fei
- Department of Hepatobiliary, Pancreatic, and Splenic Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
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Song Y, Li J. Expression profiles of serum transfer RNA-derived fragments and their potential roles in non-small cell lung cancer. Transl Cancer Res 2024; 13:3668-3677. [PMID: 39145073 PMCID: PMC11322679 DOI: 10.21037/tcr-23-2364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 05/24/2024] [Indexed: 08/16/2024]
Abstract
Background Non-small cell lung cancer (NSCLC) is one of the malignant tumors with the highest morbidity and mortality in the world. Early diagnosis can significantly improve the prognosis of patients. Transfer RNA (tRNA)-derived fragments (tRFs) have been found to have a crucial function in the pathophysiology of cancers. However, the role of tRFs/tRNA halves (tiRNAs) in NSCLC is yet unknown. The present study aimed to investigate unique expression profiles of tRFs/tiRNAs in NSCLC and search novel biomarkers for the diagnosis. Methods RNA-sequencing was utilized for determining differently expressed tRFs/tiRNAs in serum in NSCLC and healthy controls. Stem-loop quantitative polymerase chain reaction (PCR) was used to confirm the selected tRFs/tiRNAs expressions. Their possible roles in NSCLC were predicted using bioinformatic research. Results Eleven up-regulated tRFs/tiRNAs and 18 down-regulated tRFs/tiRNAs were determined. Levels of tRF-31-87R8WP9N1EWJ0 and tRF-31-79MP9P9NH57SD were significantly higher in NSCLC serum samples than those of healthy controls; the receiver operating characteristic (ROC) curve suggested that they could serve as new diagnostic biomarkers. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis hinted that tRF-31-87R8WP9N1EWJ0 and tRF-31-79MP9P9NH57SD might influence the development and manifestation of NSCLC. Conclusions In NSCLC patients' serum, the tRFs/tiRNAs were abnormally regulated and that tRF-31-87R8WP9N1EWJ0 and tRF-31-79MP9P9NH57SD might be the potential biological markers for NSCLC.
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Affiliation(s)
- Yulan Song
- Blood Purification Center, The Affiliated People’s Hospital of Ningbo University, Ningbo, China
| | - Jipeng Li
- Department of Central Laboratory, The Affiliated People’s Hospital of Ningbo University, Ningbo, China
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Mao C, Yuan W, Fang R, Wu Y, Zhang Z, Cong H. Transfer RNA‑derived small RNAs: A class of potential biomarkers in multiple cancers (Review). Oncol Lett 2024; 28:293. [PMID: 38737976 PMCID: PMC11082847 DOI: 10.3892/ol.2024.14427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/11/2024] [Indexed: 05/14/2024] Open
Abstract
Transfer (t)RNA-derived small RNAs (tsRNAs) are a class of novel non-coding small RNAs that are created via precise cleavage of tRNAs or tRNA precursors by different enzymes. tsRNAs are specific biological molecules that serve essential roles in cell proliferation, apoptosis, transcriptional regulation, post-transcriptional modification and translational regulation. Additionally, tsRNAs participate in the pathogenesis of several diseases, particularly in the development of malignant tumors. At present, the process of discovering and understanding the functions of tsRNAs is still in its early stages. The present review introduces the known biological functions and mechanisms of tsRNAs, and discusses the tsRNAs progression in several types of cancers as well as the possibility of tsRNAs becoming novel tumor biomarkers. Furthermore, tsRNAs may promote and hinder tumor formation according to different mechanisms and act as oncogenic or oncostatic molecules. Therefore, tsRNAs may be future potential tumor biomarkers or therapeutic targets.
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Affiliation(s)
- Chunyan Mao
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Clinical Medicine, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Wentao Yuan
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Clinical Medicine, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Ronghua Fang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Clinical Medicine, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yi Wu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Clinical Medicine, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Zhihan Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Clinical Medicine, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Hui Cong
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Blood Transfusion, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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Ye C, Cheng F, Huang L, Wang K, Zhong L, Lu Y, Ouyang M. New plasma diagnostic markers for colorectal cancer: transporter fragments of glutamate tRNA origin. J Cancer 2024; 15:1299-1313. [PMID: 38356701 PMCID: PMC10861818 DOI: 10.7150/jca.92102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/03/2024] [Indexed: 02/16/2024] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Early diagnosis of the disease can greatly improve the clinical prognosis for patients with CRC. Unfortunately, there are no current simple and effective early diagnostic markers available. The transfer RNA (tRNA)-derived RNA fragments (tRFs) are a class of small non-coding RNAs (sncRNAs), which have been shown to play an important role in the development and prognosis of CRC. However, only a few studies on tRFs as early diagnostic markers in CRC have been conducted. In this study, previously ignored tRFs expression data were extracted from six paired small RNA sequencing data in the Sequence Read Archive (SRA) database using MINTmap. Three i-tRFs, derived from the tRNA that transports glutamate (i-tRF-Glu), were identified and used to construct a random forest diagnostic model. The model performance was evaluated using the receiver operating characteristic (ROC) curve and precision-recall (PR) curve. The area under the curves (AUC) for the ROC and PR was 0.941 and 0.944, respectively. We further verified the differences in expression of the these i-tRF-Glu in the tissue and plasma of both CRC patients and healthy subjects using quantitative real-time PCR (qRT-PCR). We found that the ROC-AUC of the three was greater than traditional plasma tumor markers such as CEA and CA199. Our bioinformatics analysis suggested that the these i-tRF-Glu are associated with cancer development and glutamate (Glu)-glutamine (Gln) metabolism. Overall, our study uncovered these i-tRF-Glu that have early diagnostic significance and therapeutic potential for CRC, this warrants further investigation into the diagnostic and therapeutic potential of these i-tRF-Glu in CRC.
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Affiliation(s)
- Changda Ye
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Fu Cheng
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Luji Huang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Kang Wang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Lin Zhong
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Yan Lu
- GCP Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, 528300, Guangdong, China
| | - Manzhao Ouyang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
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Shi J, Xu J, Ma J, He F. tRNA-derived small RNAs are embedded in the gene regulatory network instructing Drosophila metamorphosis. Genome Res 2023; 33:2119-2132. [PMID: 37973194 PMCID: PMC10760521 DOI: 10.1101/gr.278128.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023]
Abstract
A class of noncoding RNAs, referred to as tsRNAs, is emerging with a potential to exert a new layer in gene regulation. These RNAs are breakdown products of tRNAs, either through active processing or passive cleavage or both. Since tRNAs are part of the general machinery for translation, their expression levels and activities are tightly controlled, raising the possibility that their breakdown products, tsRNAs, may provide a link between the overall translational status of a cell to specific changes in gene regulatory network. We hypothesize that Drosophila pupation, being a special developmental stage during which there is a global limitation of nutrients, represents a system in which such a link may readily reveal itself. We show that specific tsRNAs indeed show a dynamic accumulation upon entering the pupal stage. We describe experiments to characterize the mode of tsRNA action and, through the use of such gained knowledge, conduct a genome-wide analysis to assess the functions of dynamically expressed tsRNAs. Our results show that the predicted target genes are highly enriched in biological processes specific to this stage of development including metamorphosis. We further show that tsRNA action is required for successful pupation, providing direct support to the hypothesis that tsRNAs accumulated during this stage are critical to the gene expression program at this stage of development.
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Affiliation(s)
- Junling Shi
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Jiaqi Xu
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Jun Ma
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang 310058, China
- Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorder, Hangzhou, Zhejiang 310058, China
| | - Feng He
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang 310058, China
- Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorder, Hangzhou, Zhejiang 310058, China
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Du J, Huang T, Zheng Z, Fang S, Deng H, Liu K. Biological function and clinical application prospect of tsRNAs in digestive system biology and pathology. Cell Commun Signal 2023; 21:302. [PMID: 37904174 PMCID: PMC10614346 DOI: 10.1186/s12964-023-01341-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 09/27/2023] [Indexed: 11/01/2023] Open
Abstract
tsRNAs are small non-coding RNAs originating from tRNA that play important roles in a variety of physiological activities such as RNA silencing, ribosome biogenesis, retrotransposition, and epigenetic inheritance, as well as involvement in cellular differentiation, proliferation, and apoptosis. tsRNA-related abnormalities have a significant influence on the onset, development, and progression of numerous human diseases, including malignant tumors through affecting the cell cycle and specific signaling molecules. This review introduced origins together with tsRNAs classification, providing a summary for regulatory mechanism and physiological function while dysfunctional effect of tsRNAs in digestive system diseases, focusing on the clinical prospects of tsRNAs for diagnostic and prognostic biomarkers. Video Abstract.
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Affiliation(s)
- Juan Du
- Health Science Center, Ningbo University, Ningbo, 315211, Zhejiang, China
| | - Tianyi Huang
- Health Science Center, Ningbo University, Ningbo, 315211, Zhejiang, China
| | - Zhen Zheng
- Department of Radiation Oncology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Shuai Fang
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Hongxia Deng
- The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China.
| | - Kaitai Liu
- Department of Radiation Oncology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China.
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Wang XY, Zhou YJ, Chen HY, Chen JN, Chen SS, Chen HM, Li XB. 5’tiRNA-Pro-TGG, a novel tRNA halve, promotes oncogenesis in sessile serrated lesions and serrated pathway of colorectal cancer. World J Gastrointest Oncol 2023; 15:1005-1018. [PMID: 37389118 PMCID: PMC10302996 DOI: 10.4251/wjgo.v15.i6.1005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/27/2023] [Accepted: 04/17/2023] [Indexed: 06/14/2023] Open
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.
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Affiliation(s)
- Xin-Yuan Wang
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Yu-Jie Zhou
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Hai-Ying Chen
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Jin-Nan Chen
- 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
| | - Hui-Min Chen
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Xiao-Bo Li
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
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Gong M, Deng Y, Xiang Y, Ye D. The role and mechanism of action of tRNA-derived fragments in the diagnosis and treatment of malignant tumors. Cell Commun Signal 2023; 21:62. [PMID: 36964534 PMCID: PMC10036988 DOI: 10.1186/s12964-023-01079-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 02/13/2023] [Indexed: 03/26/2023] Open
Abstract
Cancer is a leading cause of morbidity and death worldwide. While various factors are established as causing malignant tumors, the mechanisms underlying cancer development remain poorly understood. Early diagnosis and the development of effective treatments for cancer are important research topics. Transfer RNA (tRNA), the most abundant class of RNA molecules in the human transcriptome, participates in both protein synthesis and cellular metabolic processes. tRNA-derived fragments (tRFs) are produced by specific cleavage of pre-tRNA and mature tRNA molecules, which are highly conserved and occur widely in various organisms. tRFs were initially thought to be random products with no physiological function, but have been redefined as novel functional small non-coding RNA molecules that help to regulate RNA stability, modulate translation, and influence target gene expression, as well as other biological processes. There is increasing evidence supporting roles for tRFs in tumorigenesis and cancer development, including the regulation of tumor cell proliferation, invasion, migration, and drug resistance. Understanding the regulatory mechanisms by which tRFs impact these processes has potential to inform malignant tumor diagnosis and treatment. Further, tRFs are expected to become new biological markers for early diagnosis and prognosis prediction in patients with tumors, as well as a targets for precision cancer therapies. Video abstract.
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Affiliation(s)
- Mengdan Gong
- Department of Otorhinolaryngology-Head and Neck Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Yongqin Deng
- Department of Otorhinolaryngology-Head and Neck Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Yizhen Xiang
- Department of Otorhinolaryngology-Head and Neck Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Dong Ye
- Department of Otorhinolaryngology-Head and Neck Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China.
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10
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Pekarsky Y, Balatti V, Croce CM. tRNA-derived fragments (tRFs) in cancer. J Cell Commun Signal 2023; 17:47-54. [PMID: 36036848 PMCID: PMC10030754 DOI: 10.1007/s12079-022-00690-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/07/2022] [Indexed: 10/15/2022] Open
Abstract
tRNA fragments (tRNA derived fragments or tRFs) are small single stranded RNA molecules derived from pre-tRNAs and mature tRNAs. tRFs have been known for a number of years, but previously they were believed to be not important products of tRNA degradation. tRFs can be unique, like tRF-1 s, or redundant, like tRF-3 s and tRF-5 s. Scientific interest in tRFs has drastically increased in the last 5 years. Many studies have found that tRFs are differentially expressed in many normal cellular processes as well as in transformed cancer cells. Dysregulation of tRFs expression have been reported in multiple major types of cancer including solid cancers and lymphoid malignancies. However the exact molecular role of these molecules is not entirely clear. A number of studies proposed that tRFs can work as microRNAs by targeting gene expression. Here we discuss recent studies showing differential expression of tRFs in many cancers as well as what is currently known about tRFs biological functions in cancer cells.
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Affiliation(s)
- Yuri Pekarsky
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Biomedical Research Tower, Room 1082, 460 West 12th Avenue, Columbus, OH, 43210, USA.
| | - Veronica Balatti
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Biomedical Research Tower, Room 1082, 460 West 12th Avenue, Columbus, OH, 43210, USA
| | - Carlo M Croce
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Biomedical Research Tower, Room 1082, 460 West 12th Avenue, Columbus, OH, 43210, USA.
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11
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Wang L, Liu Y, Yan W, Huang C, Ding Z, Yang J, Jiang S, Sun L. Clinical Significance of High Expression of tRF-Glu-TTC-2 in Prostate Carcinoma and its Effect on Growth. Am J Mens Health 2022; 16:15579883221135970. [PMID: 36377736 PMCID: PMC9673532 DOI: 10.1177/15579883221135970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The tRNA-derived fragments (tRFs) are a new class of regulatory noncoding RNAs and have different biological functions in cancer. This article investigated the expression and clinicopathological significance of tRF-Glu-TTC-2 in prostate carcinoma (PCa), and its effect on tumor growth. Expression profiles of tRFs and tiRNAs were analyzed by tRF and tiRNAs microarray in PCa samples, and then the expression was confirmed by qRT-PCR; RNA in situ hybridization was used to detect the positive expression of tRF-Glu-TTC-2 and to analyze the correlation between the expression level of tRF-Glu-TTC-2 and clinicopathological parameters. CCK-8 experiment was used to detect the effect of tRF-Glu-TTC-2 on the proliferation of PCa cells, and nude mice subcutaneous tumor model was used to detect the effect of tRF-Glu-TTC-2 on the growth of PCa cells. The results showed that tRF-Glu-TTC-2 was mainly positive and its expression level increased in PCa. The high expression was closely related to the tumor size (p < .05). Overexpression of tRF-Glu-TTC-2 promoted the proliferation of PCa cells, and decreased expression of tRF-Glu-TTC-2 inhibited the proliferation of PCa cells (p < .05). The results of subcutaneous tumor transplantation in nude mice showed that the tumor volume and weight of the knockdown group were smaller than those of the control group(all ps < .05). Ki-67 staining showed that the proportion of Ki-67-positive cells in the reduced tRF-Glu-TTC-2 group was lower than that in the control group (p < .05). The tRF-Glu-TTC-2 may be a new oncogene that can promote growth and proliferation of PCa. It provides a new idea for the treatment of PCa.
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Affiliation(s)
- Lei Wang
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, China,Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Yaxin Liu
- Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Wenqing Yan
- Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Caihong Huang
- Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Zhiyan Ding
- Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Jiajia Yang
- Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Shuwan Jiang
- Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Lei Sun
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, China,Prof. Lei Sun, Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, No. 9, west section of Lushun South Road, Dalian, Liaoning 116044, China.
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12
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Gu X, Zhang Y, Qin X, Ma S, Huang Y, Ju S. Transfer RNA-derived small RNA: an emerging small non-coding RNA with key roles in cancer. Exp Hematol Oncol 2022; 11:35. [PMID: 35658952 PMCID: PMC9164556 DOI: 10.1186/s40164-022-00290-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 05/24/2022] [Indexed: 11/10/2022] Open
Abstract
Transfer RNAs (tRNAs) promote protein translation by binding to the corresponding amino acids and transporting them to the ribosome, which is essential in protein translation. tRNA-derived small RNAs (tsRNAs) are derived fragments of tRNAs that are cleaved explicitly under certain conditions. An increasing amount of research has demonstrated that tsRNAs have biological functions rather than just being degradation products. tsRNAs can exert functions such as regulating gene expression to influence cancer progression. Their dysregulation is closely associated with various cancers and can serve as diagnostic and prognostic biomarkers for cancer. This review summarizes the generation, classification, and biological functions of tsRNAs, and highlights the roles of tsRNAs in different cancers and their applications as tumor markers.
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Affiliation(s)
- Xinliang Gu
- Medical School of Nantong University, Nantong University, Nantong, China.,Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Xisi Road, No. 20, Nantong, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yu Zhang
- Medical School of Nantong University, Nantong University, Nantong, China.,Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Xisi Road, No. 20, Nantong, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Xinyue Qin
- Medical School of Nantong University, Nantong University, Nantong, China.,Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Xisi Road, No. 20, Nantong, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Shuo Ma
- Medical School of Nantong University, Nantong University, Nantong, China.,Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Xisi Road, No. 20, Nantong, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yuejiao Huang
- Medical School of Nantong University, Nantong University, Nantong, China. .,Department of Medical Oncology, Affiliated Hospital of Nantong University, Xisi Road, No. 20, Nantong, China.
| | - Shaoqing Ju
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Xisi Road, No. 20, Nantong, China.
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13
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Context-Dependent Regulation of Gene Expression by Non-Canonical Small RNAs. Noncoding RNA 2022; 8:ncrna8030029. [PMID: 35645336 PMCID: PMC9149963 DOI: 10.3390/ncrna8030029] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/02/2022] Open
Abstract
In recent functional genomics studies, a large number of non-coding RNAs have been identified. It has become increasingly apparent that noncoding RNAs are crucial players in a wide range of cellular and physiological functions. They have been shown to modulate gene expression on different levels, including transcription, post-transcriptional processing, and translation. This review aims to highlight the diverse mechanisms of the regulation of gene expression by small noncoding RNAs in different conditions and different types of human cells. For this purpose, various cellular functions of microRNAs (miRNAs), circular RNAs (circRNAs), snoRNA-derived small RNAs (sdRNAs) and tRNA-derived fragments (tRFs) will be exemplified, with particular emphasis on the diversity of their occurrence and on the effects on gene expression in different stress conditions and diseased cell types. The synthesis and effect on gene expression of these noncoding RNAs varies in different cell types and may depend on environmental conditions such as different stresses. Moreover, noncoding RNAs play important roles in many diseases, including cancer, neurodegenerative disorders, and viral infections.
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