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.

/pdf/trna-derived-fragment-trf-glu-ttc-027-regulates-the-38ql3q23tq.pdf

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

Transfer RNA-derived fragments (tRFs) and transfer RNA halves (tiRNAs) have been shown to play crucial roles in gene regulation. This study aims to reveal the expression profiles of tRFs and tiRNAs and their possible biological roles in lung adenocarcinoma (LUAD).Five paired clinical lung adenocarcinoma tissues (LAT) and adjacent normal lung tissues (ANLT) were selected to analyze the expression of tRFs and tiRNAs. Six significantly expressed tRFs and tiRNAs were selected and validated by Quantitative Real-time PCR (qPCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed.The sequencing results showed that 109 tRFs and tiRNAs were differentially expressed between LAT and ANLT, out of which 60 were upregulated and 49 were downregulated. Compared with ANLT, lower expression levels of 3 tRF-1s (tRF-Ser-TGA-010, tRF-Arg-CCT-018, and tRF-Val-CAC-017) in LAT were verified by qPCR. Subsequently, the putative target genes of tRF-1s were analyzed by computational prediction and the top 10 significant results of GO and KEGG pathway enrichment analysis were presented.This study has revealed the landscape of tRF and tiRNA expression proﬁles in LUAD. Three newly found differentially expressed downregulated tRF-1s may be involved in the pathogenesis of LUAD and may serve as potential diagnostic biomarkers, or otherwise reconcile target genes for drug development. 

Expression profiles of tRNA-derived fragments and their potential roles in lung adenocarcinoma

Objective TRNA-derived fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs) are recognized as novel and potential types of non-coding RNAs (ncRNAs), and several tRF/tiRNA signatures are closely associated with tumor diagnosis. This study aimed to analyze the expression profiles of plasma tRFs/tiRNAs and to clarify their diagnostic value in lung adenocarcinoma (LUAD). Methods The differential expression profiles of plasma tRFs/tiRNAs in patients with four patients with early LUAD, four patients with advanced LUAD, and four healthy controls were analyzed using high-throughput sequencing technology. Then, plasma tRFs/tiRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR), and their diagnostic efficiency was appraised by receiver operating characteristic curve analysis. The correlation of candidate plasma tRFs/tiRNAs with clinicopathological features was also analyzed. Finally, bioinformatics analysis was performed to explore and identify the potential biological pathways induced by tRFs/tiRNAs. Results The sequencing results revealed that tRFs/tiRNAs from plasma samples in patients with LUAD were differently expressed, supporting the necessity of exploring their potential as biomarkers. The validation results of qRT-PCR demonstrated that the expression level of tRF-1:29-Pro-AGG-1-M6 was downregulated in LUAD, while that of tRF-55:76-Tyr-GTA-1-M2 was upregulated, which was consistent with the sequencing data. The areas under the receiver operating characteristic curve of tRF-1:29-Pro-AGG-1-M6 and tRF-55:76-Tyr-GTA-1-M2 were 0.882 and 0.896, respectively, which have significant values in the diagnosis of LUAD. The expressions of tRF-1:29-Pro-AGG-1-M6 and tRF-55:76-Tyr-GTA-1-M2 in LUAD were obviously correlated with various clinicopathological features such as tumor–node–metastasis stage, node stage, and the expression levels of carcinoembryonic antigen. In addition, their expression was significantly altered from before to after tumor resection in LUAD patients. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses further indicated that tRF-1:29-Pro-AGG-1-M6 and tRF-55:76-Tyr-GTA-1-M2 are widely distributed and apparently enriched in several tumor-related signaling pathways. Conclusions Plasma tRF-1:29-Pro-AGG-1-M6 and tRF-55:76-Tyr-GTA-1-M2 may be promising components in the development of highly sensitive and non-invasive biomarkers for LUAD diagnosis.

/pdf/plasma-trf-1-29-pro-agg-1-m6-and-trf-55-76-tyr-gta-1-m2-as-3e23aw41.pdf

Plasma tRF-1:29-Pro-AGG-1-M6 and tRF-55:76-Tyr-GTA-1-M2 as novel diagnostic biomarkers for lung adenocarcinoma

Abstract Emerging evidence indicates that transfer RNA (tRNA)‐derived small RNAs (tsRNAs), originated from tRNA with high abundance RNA modifications, play an important role in many complex physiological and pathological processes. However, the biological functions and regulatory mechanisms of modified tsRNAs in cancer remain poorly understood. Here, it is screened for and confirmed the presence of a novel m 7 G‐modified tsRNA, m 7 G‐3′‐tiRNA Lys TTT (mtiRL), in a variety of chemical carcinogenesis models by combining small RNA sequencing with an m 7 G small RNA‐modified chip. Moreover, it is found that mtiRL, catalyzed by the tRNA m 7 G‐modifying enzyme mettl1, promotes bladder cancer (BC) malignancy in vitro and in vivo. Mechanistically, mtiRL is found to specifically bind the oncoprotein Annexin A2 (ANXA2) to promote its Tyr24 phosphorylation by enhancing the interactions between ANXA2 and Yes proto‐oncogene 1 (Yes1), leading to ANXA2 activation and increased p‐ANXA2‐Y24 nuclear localization in BC cells. Together, these findings define a critical role for mtiRL and suggest that targeting this novel m 7 G‐modified tsRNA can be an efficient way for to treat BC. 

A Novel tsRNA, m7G‐3′ tiRNA LysTTT, Promotes Bladder Cancer Malignancy Via Regulating ANXA2 Phosphorylation

Understanding the pathophysiology of rheumatoid arthritis (RA) has led to the successful development of molecule-targeted drugs for the treatment of RA. However, some RA patients are refractory to these treatments, suggesting that the pathological mechanism of the disease is not entirely understood. Genome and transcriptome analysis is essential for understanding the unknown pathophysiology of human diseases. Rapid and more comprehensive gene analysis technologies have revealed notable changes in the expression of coding RNA and non-coding RNA in RA patients. This review focuses on the current state of non-coding RNA research in relation to RA, especially on tRNA fragments. Interestingly, it has been found that tRNA fragments repress translation and are antiapoptotic. The association between tRNA fragments and various diseases has been studied, and this article reviews the possible role of tRNA fragments in RA.

Possible Roles of tRNA Fragments, as New Regulatory ncRNAs, in the Pathogenesis of Rheumatoid Arthritis.

Accumulating evidence has indicated that a group of novel molecules, known as transfer RNA (tRNA)-derived fragments (tRFs) and tRNA halves (tiRNAs), which are derived from tRNAs, serve an essential role in numerous types of human disease, in particular solid tumors. However, to the best of our knowledge, the underlying mechanisms of the effect of tRFs and tiRNAs in lung adenocarcinoma have not been reported. The present study aimed to determine the differential expression levels of tRFs and tiRNAs in lung adenocarcinoma and adjacent tissues using a NextSeq system, and further investigated their potential target genes via bioinformatics analysis. Kyoto Encyclopedia of Genes and Genomes signaling pathway and Gene Ontology functional term enrichment analyses were performed to investigate the function of these target genes in the occurrence and development of lung adenocarcinoma. In patients with lung adenocarcinoma, 338 types of tRFs and tiRNAs were detected via sequencing, 284 of which were not previously reported in the tRF database. Compared with the adjacent tissues, 17 types of tRFs and tiRNAs comprising 34 subtypes were found to be abnormally expressed in lung adenocarcinoma tissues, 20 of which were upregulated and 14 downregulated. Reverse transcription-quantitative PCR verification revealed that the expression levels of tiRNA-Lys-CTT-002, tRF-Val-CAC-010 and tRF-Val-CAC-011 were significantly upregulated, while those of tRF-Ser-TGA-005 were downregulated in lung adenocarcinoma tissues. Bioinformatics analysis identified that tRF-Ser-TGA-005 participated in the 'cellular response to transforming growth factor β stimulus' and tRF-Val-CAC-010 and tRF-Val-CAC-011 participated in the 'Hedgehog signaling pathway'. In conclusion, the results of the present study suggested that tRFs and tiRNAs may be closely associated with the pathogenesis and development of lung adenocarcinoma, providing a novel insight for further studies into lung adenocarcinoma.

/pdf/screening-and-potential-role-of-trfs-and-tirnas-derived-from-3dg5drbno5.pdf

Screening and potential role of tRFs and tiRNAs derived from tRNAs in the carcinogenesis and development of lung adenocarcinoma.

Diosgenin, an essential dietary steroidal sapogenin, possess multiple pharmacological activities. This study aimed to assess the effects of diosgenin on periodontitis and elucidate the mechanisms. Lipopolysaccharide (LPS)-stimulated human periodontal ligament stem cells (hPDLCs) and a Porphyromonas gingivalis (P.g) plus ligation-induced animal model were used for in vitro and in vivo studies, respectively. Inflammatory responses, nuclear factor κ-B (NF-κB) signaling and osteogenesis-related markers were measured both in LPS-stimulated hPDLSCs and in gingival tissue of periodontitis rats. Treatment with diosgenin significantly inhibited the production of tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and interleukin (IL)-6 and the activation of NF-κB pathway in LPS-stimulated hPDLSCs. Further, treatment with diosgenin enhanced the expression of osteoblast-related genes and increased the osteogenic differentiation capacity. Further, activation NF-κB pathway largely abolished the protective effects of diosgenin. Consistent with the in vitro studies, in vivo studies showed that administering diosgenin to periodontitis rats significantly lowered the levels of the TNF-α, IL-1β, and IL-6 and the inflammatory transcription factor NF-κB in gingival tissue. In addition, osteoblast-related genes were promoted. Diosgenin attenuates periodontitis by adjusting NF-κB signaling to inhibit inflammatory effects and promoting osteogenesis, suggesting diosgenin might be developed as a therapeutic strategy for treating periodontitis in the future. 

Diosgenin prevents periodontitis by inhibiting inflammation and promoting osteogenic differentiation.

Human bone marrow mesenchymal stem cells (h-BMSCs) have the potential to differentiate into dopaminergic neuron-like cells to treat Parkinson's disease. The Notch signaling pathway has been implicated in the regulation of cell fate decisions such as differentiation of BMSCs. This study investigated changes in the expression of Notch-related genes in the differentiation of BMSCs in vitro into dopaminergic (DA) neuron-like cells. BMSCs transfected with empty lentiviral vectors served as the control group and those transfected with NTN and Lmx1α recombinant lentiviral vectors served as the experimental group. After induction and culture of NTN and Lmx1α-transfected h-BMSCs for 21 days, the cells exhibited features of dopaminergic neuron-like cells, which were observed by transmission and scanning electron microscopy and verified by immunofluorescence of tyrosine hydroxylase (TH) and dopamine transporter (DAT). These induced cells could secrete dopamine and had basic action potentials. Expression of the neural stem cell (NSC) markers, including octamer-binding protein (Oct4), paired box gene 6 (Pax6), and sex determining region Y-box 1 (SOX1), increased on day 14 of induction and decreased on day 21 of induction during differentiation. The human Notch signaling pathway PCR array showed a differential expression of Notch-related genes during the differentiation of h-BMSCs into DA neuron-like cells in vitro relative to that in the control group. In conclusion, h-BMSCs overexpressing NTN and Lmx1α can successfully be induced to differentiate into dopaminergic neuron-like cells with a neuronal phenotype exhibiting fundamental biological functions in vitro, and NTN and Lmx1α may affect the expression of Notch-related genes during differentiation.

/pdf/effect-of-ntn-and-lmx1a-on-the-notch-signaling-pathway-2kvvlari2z.pdf

Effect of NTN and Lmx1α on the Notch Signaling Pathway during the Differentiation of Human Bone Marrow Mesenchymal Stem Cells into Dopaminergic Neuron-Like Cells.

Background: Epigenetic regulation plays significant role in the development of the inner ear. It is known that Ring1B can monoubiquitinate H2AK119 to compact nucleosomes and block gene transcription. Ring1B plays crucial role in embryonic development, heterochromatin function, stem cell maintenance and so on. However, it is still unknown whether Ring1B plays a role in the development of inner ear. Methods: Here, we used postnatal C56BL/6J mice to examine the expression of Ring1B in the cochlea using real-time quantitative polymerase chain reaction, Western blot, and immunofluorescence staining. Results: Ring1B mRNA expression was observed at postnatal day 0 and postnatal day 14 cochlea. Ring1B protein was expressed in the cochlea on postnatal days 0, 14, and 30. The Ring1B was observed to be expressed in spiral ganglion cells at postnatal days 0, 14, and 30. Additionally, Ring1B was expressed in hair cells at postnatal days 0, 14, and 30. Conclusion: Our results provide the basic expression pattern of Ring1B and might be helpful for future investigations of the detailed role of Ring1B in the cochlea.

The Spatiotemporal Expression of Ring1B in the Postnatal Mouse Cochlea

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Papers

Screening and potential role of tRFs and tiRNAs derived from tRNAs in the carcinogenesis and development of lung adenocarcinoma.

Diosgenin prevents periodontitis by inhibiting inflammation and promoting osteogenic differentiation.

Effect of NTN and Lmx1α on the Notch Signaling Pathway during the Differentiation of Human Bone Marrow Mesenchymal Stem Cells into Dopaminergic Neuron-Like Cells.

The Spatiotemporal Expression of Ring1B in the Postnatal Mouse Cochlea