Dicer1 Promotes Colon Cancer Cell Invasion and Migration Through Modulation of tRF-20-MEJB5Y13 Expression Under Hypoxia

Luan, Na; Mu, Yali; Mu, Jiayi; Chen, Yiquan; Ye, Xun; Zhou, Qin; Xu, Miaorong; Deng, Qun; Hu, Yeting; Tang, Zhe; Wang, Jianwei

doi:10.3389/fgene.2021.638244

Cited by 28 publications

(25 citation statements)

References 32 publications

(24 reference statements)

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“…There were signi cant differences in the expression of different tRFs under hypoxic conditions. Among the differentially expressed tRFs, two signi cantly downregulated tRFs (tRF-20-M0NK5Y93, tRF-21-3OPP6N7KE) and one signi cantly upregulated tRF (tRF-20-MEJB5Y13) showed the most obvious expression differences, which were consistent with the trend of sequencing results (see the basis of previous work) [24,25]. All three types of tRFs are derived from tRNAs corresponding to different codons for arginine (Arg).…”

Section: Introductionsupporting

confidence: 87%

NSUN2-Mediated Splice Site m5C Methylation Modification Promotes the Progression of Colon Cancer Through Modulating the Discrepant Cleavage of tRNA-Arg

Luan

Cao

Sun

et al. 2021

Preprint

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Background: Hypoxia is a key driving factor for the tumour microenvironment restructuring, which leading to the variation of gene expression profiling in cancer cells. Increasing evidence reveals the initial action of hypoxia in the epitranscriptomics including RNA methylation. The role of tRNA-derived fragments (tRFs) in regulating tumour metastasis potential has attracted attention. Methods: The expression of tRFs in colon cancer cells under hypoxia were evaluated based on full-transcript sequencing and bioinformatics analysis and their effects on colon cancer metastasis were detected by transwell assays. The role of C34 was verified by introducing mutation and artificial m5C modification. The effects of NSUN2 on the biological characteristics of colon cancer cells were investigated on the basis of gain-of-function and loss-of function analyses. Lung metastasis model further uncovered the roles of NSUN2 and key tRF in tumour progression. Assays of RNA immunoprecipitation-qPCR (RIP-qPCR) were performed to identify that NSUN2 is a key methyltransferase for cysteine modification at C34 of tRNA-Arg.Results: The present study verified the up-expression of tRF (tRF-20-MEJB5Y13) and down-expression of tRFs (tRF-20-M0NK5Y93 and tRF-21-3OPP6N7KE) in colon cancer cells under hypoxia, and all of them were derived from different tRNA-Arg. Contradictory effects of these three tRNA-Arg-derived tRFs on metastatic potential of colon cancer were demonstrated in this study. The sequence differences and the key nucleotide bases of tRNA with the methylation modification potential among the source tRNAs were analysed. Notably, our data identified C34 of tRNA-Arg as a key site that may play an important role in hypoxia-mediated tRNA-Arg discrepant cleavage. We further investigated that NSUN2 mediated specific site methylation of tRNA-Arg at C34, thereby protecting tRNA from cleavage by endonuclease and subsequently promoting the colon cancer metastasis both in vitro and in vivo. Conclusion: The present study elaborates on the precise regulatory mechanism of m5C methylation and the role in the selective cleavage of tRNA from the perspective of noncoding RNA methylation epitranscriptomics, providing a novel insight into the molecular basis of selective expression of tRFs in colon cancer under hypoxia.

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Section: Introductionsupporting

confidence: 87%

NSUN2-Mediated Splice Site m5C Methylation Modification Promotes the Progression of Colon Cancer Through Modulating the Discrepant Cleavage of tRNA-Arg

Luan

Cao

Sun

et al. 2021

Preprint

Self Cite

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“…They are involved in the cell cycle, proliferation, cell apoptosis, and many other biological regulation pathways (15). Many pieces of literature reported that tRFs are actively derived from precursor RNAs and the 3' or 5' end-matching tRFs are largely cleaved by Dicer1 owing to their structural features (7,16). Meanwhile, considering the bind method between tRFs and mRNA of the target genes, Kuscu et al showed that Dicer-independent tRF-3s could suppress the posttranscription of genes by an Argonaute-RISC method, which had a certain degree of similarity with miRNAs (17).…”

Section: Discussionmentioning

confidence: 99%

tRNA-Derived Fragment tRF-Glu-TTC-027 Regulates the Progression of Gastric Carcinoma via MAPK Signaling Pathway

Zhou

Wang

et al. 2021

Front. Oncol.

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Transfer RNA-derived RNA fragments (tRFs) belong to non-coding RNAs (ncRNAs) discovered in most carcinomas. Although some articles have demonstrated the characteristics of tRFs in gastric carcinoma (GC), the underlying mechanisms still need to be elucidated. Meanwhile, it was reported that the MAPK pathway was momentous in GC progression. Thus we focused on investigating whether tRF-Glu-TTC-027 could act as a key role in the progression of GC with the regulation of the MAPK pathway. We collected the data of the tRNA-derived fragments expression profile from six paired clinical GC tissues and corresponding adjacent normal samples in this study. Then we screened tRF-Glu-TTC-027 for analysis by using RT-PCR. We transfected GC cell lines with tRF-Glu-TTC-027 mimics or mimics control. Then the proliferation, migration, and invasion assays were performed to assess the influence of tRF-Glu-TTC-027 on GC cell lines. Fluorescence in situ hybridization assay was conducted to confirm the cell distribution of tRF-Glu-TTC-027. We confirmed the mechanism that tRF-Glu-TTC-027 influenced the MAPK signaling pathway and observed a strong downregulation of tRF-Glu-TTC-027 in clinical GC samples. Overexpression of tRF-Glu-TTC-027 suppressed the malignant activities of GC in vitro and in vivo. MAPK signaling pathway was confirmed to be a target pathway of tRF-Glu-TTC-027 in GC by western blot. This is the first study to show that tRF-Glu-TTC-027 was a new tumor-suppressor and could be a potential object for molecular targeted therapy in GC.

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“…Its stable structure and high expression in body fluids make it relatively easy to detect, which makes it possible to become a new potential biomarker for tumors. Currently, most studies on tsRNAs have described the effects on proliferation, invasion, and migration of tumor cells and the mechanisms involved in hypoxia and epithelial to mesenchymal transformation (EMT) ( 10 , 21 , 51 , 52 ). However, there are few studies on whether tsRNAs can be used as a biomarker for tumors ( 18 , 24 , 53 ).…”

Section: Discussionmentioning

confidence: 99%

Elucidating the Role of Serum tRF-31-U5YKFN8DYDZDD as a Novel Diagnostic Biomarker in Gastric Cancer (GC)

Huang

Zhang

et al. 2021

Front. Oncol.

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BackgroundGastric cancer (GC) is one of the malignant tumors with the highest morbidity and mortality in the world. Early diagnosis combined with surgical treatment can significantly improve the prognosis of patients. Therefore, it is urgent to seek higher sensitivity and specificity biomarkers in GC. tRNA-derived small RNAs are a new non-coding small RNA that widely exists in tumor cells and body fluids. In this study, we explore the expression and biological significance of tRNA-derived small RNAs in GC.Materials and MethodsFirst of all, we screened the differentially expressed tRNA-derived small RNAs in tumor tissues by high-throughput sequencing. Agarose gel electrophoresis (AGE), Sanger sequencing, and Nuclear and Cytoplasmic RNA Separation Assay were used to screen tRF-31-U5YKFN8DYDZDD as a potential tumor biomarker for the diagnosis of GC. Then, we detected the different expressions of tRF-31-U5YKFN8DYDZDD in 24 pairs of GC and paracancerous tissues, the serum of 111 GC patients at first diagnosis, 89 normal subjects, 48 superficial gastritis patients, and 28 postoperative GC patients by quantitative real-time PCR (qRT-PCR). Finally, we used the receiver operating characteristic (ROC) curve to analyze its diagnostic efficacy.ResultsThe expression of tRF-31-U5YKFN8DYDZDD has good stability and easy detection. tRF-31-U5YKFN8DYDZDD was highly expressed in tumor tissue, serum, and cell lines of GC, and the expression was significantly related to TNM stage, depth of tumor invasion, lymph node metastasis, and vascular invasion. The expression of serum tRF-31-U5YKFN8DYDZDD in the GC patients decreased after the operation (P = 0.0003). Combined with ROC curve analysis, tRF-31-U5YKFN8DYDZDD has better detection efficiency than conventional markers.ConclusionsThe expressions of tRF-31-U5YKFN8DYDZDD in the tumor and paracancerous tissues, the serum of GC patients and healthy people, and the serum of GC patients before and after operation were different. tRF-31-U5YKFN8DYDZDD is not only a diagnostic biomarker of GC but also a predictor of poor prognosis.

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Dicer1 Promotes Colon Cancer Cell Invasion and Migration Through Modulation of tRF-20-MEJB5Y13 Expression Under Hypoxia

Cited by 28 publications

References 32 publications

NSUN2-Mediated Splice Site m5C Methylation Modification Promotes the Progression of Colon Cancer Through Modulating the Discrepant Cleavage of tRNA-Arg

NSUN2-Mediated Splice Site m5C Methylation Modification Promotes the Progression of Colon Cancer Through Modulating the Discrepant Cleavage of tRNA-Arg

tRNA-Derived Fragment tRF-Glu-TTC-027 Regulates the Progression of Gastric Carcinoma via MAPK Signaling Pathway

Elucidating the Role of Serum tRF-31-U5YKFN8DYDZDD as a Novel Diagnostic Biomarker in Gastric Cancer (GC)

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