Small non-coding RNAs as diagnostic, prognostic and predictive biomarkers of gynecological cancers: an update.

INTRODUCTION: Non-coding RNAs (ncRNAs) comprise a heterogeneous cluster of RNA molecules. Emerging evidence suggests their involvement in various aspects of tumorigenesis, particularly in gynecological malignancies. Notably, ncRNAs have been implicated as mediators within tumor signaling pathways, exerting their influence through interactions with RNA or proteins. These findings further highlight the hypothesis that ncRNAs constitute therapeutic targets and point out their clinical potential as stratification biomarkers. AREAS COVERED: The review outlines the use of small ncRNAs, including miRNAs, tRNA-derived small RNAs, PIWI-interacting RNAs and circular RNAs, for diagnostic, prognostic, and predictive purposes in gynecological cancers. It aims to increase our knowledge of their functions in tumor biology and their translation into clinical practice. EXPERT OPINION: By leveraging interdisciplinary collaborations, scientists can decipher the riddle of small ncRNA biomarkers as diagnostic, prognostic and predictive biomarkers of gynecological tumors. Integrating small ncRNA-based assays into clinical practice will allow clinicians to provide cure plans for each patient, reducing the likelihood of adverse responses. Nevertheless, addressing challenges such as standardizing experimental methodologies and refining diagnostic assays is imperative for advancing small ncRNA research in gynecological cancer.

The subcellular distribution of miRNA isoforms, tRNA-derived fragments, and rRNA-derived fragments depends on nucleotide sequence and cell type.

BACKGROUND: MicroRNA isoforms (isomiRs), tRNA-derived fragments (tRFs), and rRNA-derived fragments (rRFs) represent most of the small non-coding RNAs (sncRNAs) found in cells. Members of these three classes modulate messenger RNA (mRNA) and protein abundance and are dysregulated in diseases. Experimental studies to date have assumed that the subcellular distribution of these molecules is well-understood, independent of cell type, and the same for all isoforms of a sncRNA. RESULTS: We tested these assumptions by investigating the subcellular distribution of isomiRs, tRFs, and rRFs in biological replicates from three cell lines from the same tissue and same-sex donors that model the same cancer subtype. In each cell line, we profiled the isomiRs, tRFs, and rRFs in the nucleus, cytoplasm, whole mitochondrion (MT), mitoplast (MP), and whole cell. Using a rigorous mathematical model we developed, we accounted for cross-fraction contamination and technical errors and adjusted the measured abundances accordingly. Analyses of the adjusted abundances show that isomiRs, tRFs, and rRFs exhibit complex patterns of subcellular distributions. These patterns depend on each sncRNA's exact sequence and the cell type. Even in the same cell line, isoforms of the same sncRNA whose sequences differ by a few nucleotides (nts) can have different subcellular distributions. CONCLUSIONS: SncRNAs with similar sequences have different subcellular distributions within and across cell lines, suggesting that each isoform could have a different function. Future computational and experimental studies of isomiRs, tRFs, and rRFs will need to distinguish among each molecule's various isoforms and account for differences in each isoform's subcellular distribution in the cell line at hand. While the findings add to a growing body of evidence that isomiRs, tRFs, rRFs, tRNAs, and rRNAs follow complex intracellular trafficking rules, further investigation is needed to exclude alternative explanations for the observed subcellular distribution of sncRNAs.

Semen sEV tRF-Based Models Increase Non-Invasive Prediction Accuracy of Clinically Significant Prostate Cancer among Patients with Moderately Altered PSA Levels.

PSA screening has led to an over-diagnosis of prostate cancer (PCa) and unnecessary biopsies of benign conditions due to its low cancer specificity. Consequently, more accurate, preferentially non-invasive, tests are needed. We aim to evaluate the potential of semen sEV (small extracellular vesicles) tsRNAs (tRNA-derived small RNAs) as PCa indicators. Initially, following a literature review in the OncotRF database and high-throughput small RNA-sequencing studies in PCa tissue together with the sncRNA profile in semen sEVs, we selected four candidate 5'tRF tsRNAs for validation as PCa biomarkers. RT-qPCR analysis in semen sEVs from men with moderately elevated serum PSA levels successfully shows that the differential expression of the four tRFs between PCa and healthy control groups can be detected in a non-invasive manner. The combined model incorporating PSA and specific tRFs (5'-tRNA-Glu-TTC-9-1_L30 and 5'-tRNA-Val-CAC-3-1_L30) achieved high predictive accuracy in identifying samples with a Gleason score ≥ 7 and staging disease beyond IIA, supporting that the 5'tRF fingerprint in semen sEV can improve the PSA predictive value to discriminate between malignant and indolent prostate conditions. The in silico study allowed us to map target genes for the four 5'tRFs possibly involved in PCa. Our findings highlight the synergistic use of multiple biomarkers as an efficient approach to improve PCa screening and prognosis.

A versatile and efficient method for detecting tRNA-derived fragments.

Recently, it has been discovered surprisingly that tRNA can be cleaved into specific small fragments under certain conditions. Most importantly, these tRNA-derived fragments (tRFs) participate in the regulation of gene expression, playing pivotal roles in various physiological and pathological processes and thus attracting widespread attention. Detecting tRF expression in tissues and cells often involves using tRF-specific stem-loop primers for reverse transcription. However, the high specificity offered by this method limits it to transcribing only one specific tRF sequence per reaction, necessitating separate reverse transcription and qPCR steps for multiple tRFs, leading to substantially increased time and resource consumption. This becomes especially challenging in precious samples with limited RNA availability. To address these issues, there is an urgent need for a universal and cost-effective tRF identification method. This study introduces a versatile tRF detection approach based on the uniform polyadenylation of all tRFs, allowing reverse transcription with a universal oligo(dT) primer. This method enables simultaneous reverse transcription of all target tRFs in one reaction, greatly facilitating subsequent qPCR analysis. Furthermore, it demonstrates exceptional sensitivity and specificity, offering significant value in tRF-related research.

Expression profiles of serum transfer RNA-derived fragments and their potential roles in non-small cell lung cancer.

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.

Circulating Exosomal Transfer RNA-Related Fragments as Diagnostic Biomarkers for Non-small Cell Lung Cancer.

PURPOSE: Exosomal transfer RNA-derived fragments [exo-tRF] possess the capacity to be employed as biomarkers for several types of cancer. We aim to ascertain the diagnostic significance of exosomal 5'tRF-TyrGTA and 5'tRF-ValTAC in non-small cell lung cancer [NSCLC]. METHODS: Ultracentrifugation was deployed to obtain serum exosomes from NSCLC patients and healthy donors. The acquired exosomes were then confirmed by transmission electron microscopy [TEM], qNano, and western blot [WB] techniques. The level of exo- tRF expression was validated by the use of microarrays and RT-qPCR. The diagnostic performance of exo-tRFs for NSCLC was determined through the receiver operating characteristic curve [ROC]. RESULTS: Exosomal 5'tRF-TyrGTA and 5'tRF-ValTAC were significantly downregulated in both early- and late-stage NSCLC patients compared to healthy donors, representing favorable diagnostic efficiency for NSCLC. In addition, the exosomal 5'tRF-TyrGTA level was correlated with tumor stage and lymph node metastasis. CONCLUSION: Exosomal 5'tRF-TyrGTA and 5'tRF-ValTAC can serve as potential biomarkers for NSCLC.

In Silico Identification of tRNA Fragments, Novel Candidates for Cancer Biomarkers, and Therapeutic Targets.

The identification of a wide variety of RNA molecules using high-throughput sequencing techniques in the transcriptome pool of living organisms has revealed hidden regulatory insights in the cell. The class of non-coding RNA fragments produced from transfer RNA, or tRFs, is one such example. They are heterogeneously sized molecules with lengths ranging between 15 and 50 nt. They have a history of being dysregulated in human malignancies and other illnesses. The detection of these molecules has been made easier by a variety of bioinformatics techniques. The various types of tRFs and how they relate to cancer are covered in this chapter. It also provides a summary of the biological significance of tRFs reported in human cancer. Additionally, it emphasizes the utilities of databases and computational tools that have been created by different research teams for the investigation of tRFs. This will further aid the exploration and analysis of tRFs in cancer research and will support future advancement and a better comprehension of these molecules.

The function and therapeutic potential of transfer RNA-derived small RNAs in cardiovascular diseases: A review.

Transfer RNA-derived small RNAs (tsRNAs) are a class of small non-coding RNA (sncRNA) molecules derived from tRNA, including tRNA derived fragments (tRFs) and tRNA halfs (tiRNAs). tsRNAs can affect cell functions by participating in gene expression regulation, translation regulation, intercellular signal transduction, and immune response. They have been shown to play an important role in various human diseases, including cardiovascular diseases (CVDs). Targeted regulation of tsRNAs expression can affect the progression of CVDs. The tsRNAs induced by pathological conditions can be detected when released into the extracellular, giving them enormous potential as disease biomarkers. Here, we review the biogenesis, degradation process and related functional mechanisms of tsRNAs, and discuss the research progress and application prospects of tsRNAs in different CVDs, to provide a new perspective on the treatment of CVDs.

Serum exosome tRFs as a promising biomarker for active tuberculosis and latent tuberculosis infection.

OBJECTIVE: To analyse the expression profiles of serum exosome tRFs/tiRNAs and to explore their diagnostic value in tuberculosis (TB) activity. METHODS: The serum exosome tRF/tiRNA profile was analysed using high-throughput sequencing technology in 5 active tuberculosis (ATB) patients, 5 latent tuberculosis infection (LTBI) patients and 5 healthy controls (HCs). Then, serum exosome tRFs/tiRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR), and their diagnostic value was evaluated by receiver operating characteristic curve (ROC) and area under the curve (AUC). Finally, bioinformatics analysis was performed to explore and identify the potential biological pathways induced by tRFs/tiRNAs. RESULTS: The sequencing results revealed that serum exosome tRF/tiRNA expression profiles were different among ATB patients, LTBI patients and HCs. Three tRFs (tRF-56:75-Trp-CCA-4, tRF-1:22-chrM.Ser-GCT and tRF-56:76-Val-TAC-1-M2) were selected for qRT-PCR validation. The results demonstrated that the expression level of tRF-1-22-chrM.Ser-GCT was upregulated in ATB patients, while tRF-56-75-Trp-CCA-4 was downregulated, which was consistent with the sequencing data. The AUCs of tRF-56:75-Trp-CCA-4 and tRF-1:22-chrM. Ser-GCT were 0.824 and 1.000, respectively, which have significant values in the diagnosis of ATB patients. Moreover, the expression levels of tRF-56:75-Trp-CCA-4 and tRF-1:22-chrM.Ser-GCT and tRF-56:76-Val-TAC-1-M2 in ATB patients and LTBI were different, which indicated that these three tRFs could effectively distinguish ATB patients and LTBI patients. CONCLUSION: Our findings indicate that serum exosome tRFs can be used as potential markers for the diagnosis of ATB and LTBI.

Differential expression profiles and bioinformatics analysis of tRNA-derived small RNAs in epicardial fat of patients with atrial fibrillation.

The exact processes underlying atrial fibrillation (AF) are still unclear. It has been suggested that epicardial adipose tissue (EAT) may contribute to arrhythmias and can release various bioactive molecules, including exosomes containing tRNA-derived small RNAs (tsRNAs). Numerous studies have indicated that these tsRNAs can significantly affect key cellular functions. However, there is currently no research investigating the relationship between tsRNAs from EAT and AF. In order to explore the regulatory mechanisms of tsRNAs from EAT associated with AF, we conducted RNA-sequencing analysis on EAT samples collected from 6 AF patients and 6 control subjects with sinus rhythm. Our analysis revealed an upregulation of 146 tsRNAs and a downregulation of 126 tsRNAs in AF. Furthermore, we randomly selected four tsRNAs (tRF-SeC-TCA-001, tiRNA-Gly-CCC-003, tRF-Gly-GCC-002, and tRF-Tyr-GTA-007) for validation using quantitative reverse transcription-polymerase chain reaction. Following this, bioinformatic analyses revealed that the target genes of these tsRNAs were prominently involved in the regulation of cell adhesion and various cellular processes mediated by plasma membrane adhesion molecules. Additionally, based on KEGG analysis, it was suggested that the majority of these target genes might contribute to the pathogenesis of AF through processes such as glycosaminoglycan biosynthesis, AMP-activated protein kinase activity, and the insulin signaling pathway. Our results elucidate changes in the expression profiles of tsRNAs within EAT samples obtained from AF patients, and they forecast potential target genes and interactions between tsRNAs and mRNA within EAT that could contribute to the pathogenesis of AF.

Fluorescence in depth: integration of spectroscopy and imaging with Raman, IR, and CD for advanced research.

Fluorescence spectroscopy serves as a vital technique for studying the interaction between light and fluorescent molecules. It encompasses a range of methods, each presenting unique advantages and applications. This technique finds utility in various chemical studies. This review discusses Fluorescence spectroscopy, its branches such as Time-Resolved Fluorescence Spectroscopy (TRFS) and Fluorescence Lifetime Imaging Microscopy (FLIM), and their integration with other spectroscopic methods, including Raman, Infrared (IR), and Circular Dichroism (CD) spectroscopies. By delving into these methods, we aim to provide a comprehensive understanding of the capabilities and significance of fluorescence spectroscopy in scientific research, highlighting its diverse applications and the enhanced understanding it brings when combined with other spectroscopic methods. This review looks at each technique's unique features and applications. It discusses the prospects of their combined use in advancing scientific understanding and applications across various domains.

The floral development of the allotetraploid Coffea arabica L. correlates with a small RNA dynamic reprogramming.

Noncoding and coding RNAs are key regulators of plant growth, development, and stress responses. To investigate the types of transcripts accumulated during the vegetative to reproductive transition and floral development in the Coffea arabica L., we sequenced small RNA libraries from eight developmental stages, up to anthesis. We combined these data with messenger RNA and PARE sequencing of two important development stages that marks the transition of an apparent latent to a rapid growth stage. In addition, we took advantage of multiple in silico tools to characterize genomic loci producing small RNAs such as phasiRNAs, miRNAs, and tRFs. Our differential and co-expression analysis showed that some types of small RNAs such as tRNAs, snoRNAs, snRNAs, and phasiRNAs preferentially accumulate in a stage-specific manner. Members of the miR482/miR2118 superfamily and their 21-nucleotide phasiRNAs originating from resistance genes show a robust co-expression pattern that is maintained across all the evaluated developmental stages. Finally, the majority of miRNAs accumulate in a family stage-specific manner, related to modulated hormonal responses and transcription factor expression.

In silico approach for the identification of tRNA-derived small non-coding RNAs in SARS-CoV infection.

tsRNAs (tRNA-derived small non-coding RNAs), including tRNA halves (tiRNAs) and tRNA fragments (tRFs), have been implicated in some viral infections, such as respiratory viral infections. However, their involvement in SARS-CoV infection is completely unknown. A comprehensive analysis was performed to determine tsRNA populations in a mouse model of SARS-CoV-infected samples containing the wild-type and attenuated viruses. Data from the Gene Expression Omnibus (GEO) dataset at NCBI (accession ID GSE90624 ) was used for this study. A count matrix was generated for the tRNAs. Differentially expressed tRNAs, followed by tsRNAs derived from each significant tRNAs at different conditions and time points between the two groups WT(SARS-CoV-MA15-WT) vs Mock and ΔE (SARS-CoV-MA15-ΔE) vs Mock were identified. Notably, significantly differentially expressed tRNAs at 2dpi but not at 4dpi. The tsRNAs originating from differentially expressed tRNAs across all the samples belonging to each condition (WT, ΔE, and Mock) were identified. Intriguingly, tRFs (tRNA-derived RNA fragments) exhibited higher levels compared to tiRNAs (tRNA-derived stress-induced RNAs) across all samples associated with WT SARS-CoV strain compared to ΔE and mock-infected samples. This discrepancy suggests a non-random formation of tsRNAs, hinting at a possible involvement of tsRNAs in SARS-CoV viral infection.

Small RNA-seq and clinical evaluation of tRNA-derived fragments in multiple myeloma: Loss of mitochondrial i-tRFHisGTG results in patients' poor treatment outcome.

Despite the substantial progress in multiple myeloma (MM) therapy nowadays, treatment resistance and disease relapse remain major clinical hindrances. Herein, we have investigated tRNA-derived fragment (tRF) profiles in MM and precursor stages (smoldering MM/sMM; monoclonal gammopathy of undetermined significance/MGUS), aiming to unveil potential MM-related tRFs in ameliorating MM prognosis and risk stratification. Small RNA-seq was performed to profile tRFs in bone marrow CD138+ plasma cells, revealing the significant deregulation of the mitochondrial internal tRFHisGTG (mt-i-tRFHisGTG) in MM versus sMM/MGUS. The screening cohort of the study consisted of 147 MM patients, and mt-i-tRFHisGTG levels were quantified by RT-qPCR. Disease progression was assessed as clinical end-point for survival analysis, while internal validation was performed by bootstrap and decision curve analyses. Screening cohort analysis highlighted the potent association of reduced mt-i-tRFHisGTG levels with patients' bone disease (p = 0.010), osteolysis (p = 0.023) and with significantly higher risk for short-term disease progression following first-line chemotherapy, independently of patients' clinical data (HR = 1.954; p = 0.036). Additionally, mt-i-tRFHisGTG-fitted multivariate models led to superior risk stratification of MM patients' treatment outcome and prognosis compared to disease-established markers. Notably, our study highlighted mt-i-tRFHisGTG loss as a powerful independent indicator of post-treatment progression of MM patients, leading to superior risk stratification of patients' treatment outcome.

Structural determinants for tRNA selective cleavage by RNase 2/EDN.

tRNA-derived fragments (tRFs) have emerged as key players of immunoregulation. Some RNase A superfamily members participate in the shaping of the tRFs population. By comparing wild-type and knockout macrophage cell lines, our previous work revealed that RNase 2 can selectively cleave tRNAs. Here, we confirm the in vitro protein cleavage pattern by screening of synthetic tRNAs, single-mutant variants, and anticodon-loop DNA/RNA hairpins. By sequencing of tRF products, we identified the cleavage selectivity of recombinant RNase 2 with base specificity at B1 (U/C) and B2 (A) sites, consistent with a previous cellular study. Lastly, protein-hairpin complexes were predicted by MD simulations. Results reveal the contribution of the α1, loop 3 and loop 4, and ß6 RNase 2 regions, where residues Arg36/Asn39/Gln40/Asn65/Arg68/Arg132 provide interactions, spanning from P-1 to P2 sites that are essential for anticodon loop recognition. Knowledge of RNase 2-specific tRFs generation might guide new therapeutic approaches for infectious and immune-related diseases.

Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via ß-Klotho and perilipin 2.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5'tRF transfer RNA fragments and microRNA miR-194-5p. METHODS: Combined use of diet induced obese mice with human-derived oleic acid-exposed Hep G2 cells revealed new NAFLD roles of LysTTT-5'tRF and miR-194-5p. RESULTS: Unlike lean animals, dietary-induced NAFLD mice showed concurrent hepatic decrease of both LysTTT-5'tRF and miR-194-5p levels, which were restored following miR-132 antisense oligonucleotide treatment which suppresses hepatic steatosis. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5'tRF levels while increasing lipid accumulation. Inversely, transfecting fattened cells with a synthetic LysTTT-5'tRF mimic elevated mRNA levels of the metabolic regulator ß-Klotho while decreasing triglyceride amounts by 30% within 24 h. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug-repurposing compounds, Danazol and Latanoprost, elevated miR-194-5p or LysTTT-5'tRF levels. CONCLUSION: Our findings highlight the different yet complementary roles of miR-194-5p and LysTTT-5'tRF and offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.

The Typical tRNA Co-Expresses Multiple 5' tRNA Halves Whose Sequences and Abundances Depend on Isodecoder and Isoacceptor and Change with Tissue Type, Cell Type, and Disease.

Transfer RNA-derived fragments (tRFs) are noncoding RNAs that arise from either mature transfer RNAs (tRNAs) or their precursors. One important category of tRFs comprises the tRNA halves, which are generated through cleavage at the anticodon. A given tRNA typically gives rise to several co-expressed 5'-tRNA halves (5'-tRHs) that differ in the location of their 3' ends. These 5'-tRHs, even though distinct, have traditionally been treated as indistinguishable from one another due to their near-identical sequences and lengths. We focused on co-expressed 5'-tRHs that arise from the same tRNA and systematically examined their exact sequences and abundances across 10 different human tissues. To this end, we manually curated and analyzed several hundred human RNA-seq datasets from NCBI's Sequence Run Archive (SRA). We grouped datasets from the same tissue into their own collection and examined each group separately. We found that a given tRNA produces different groups of co-expressed 5'-tRHs in different tissues, different cell lines, and different diseases. Importantly, the co-expressed 5'-tRHs differ in their sequences, absolute abundances, and relative abundances, even among tRNAs with near-identical sequences from the same isodecoder or isoacceptor group. The findings suggest that co-expressed 5'-tRHs that are produced from the same tRNA or closely related tRNAs have distinct, context-dependent roles. Moreover, our analyses show that cell lines modeling the same tissue type and disease may not be interchangeable when it comes to experimenting with tRFs.

The Fate and Functionality of Alien tRNA Fragments in Culturing Medium and Cells of Escherichia coli.

Numerous observations have supported the idea that various types of noncoding RNAs, including tRNA fragments (tRFs), are involved in communications between the host and its microbial community. The possibility of using their signaling function has stimulated the study of secreted RNAs, potentially involved in the interspecies interaction of bacteria. This work aimed at identifying such RNAs and characterizing their maturation during transport. We applied an approach that allowed us to detect oligoribonucleotides secreted by Prevotella copri (Segatella copri) or Rhodospirillum rubrum inside Escherichia coli cells. Four tRFs imported by E. coli cells co-cultured with these bacteria were obtained via chemical synthesis, and all of them affected the growth of E. coli. Their successive modifications in the culture medium and recipient cells were studied by high-throughput cDNA sequencing. Instead of the expected accidental exonucleolysis, in the milieu, we observed nonrandom cleavage by endonucleases continued in recipient cells. We also found intramolecular rearrangements of synthetic oligonucleotides, which may be considered traces of intermediate RNA circular isomerization. Using custom software, we estimated the frequency of such events in transcriptomes and secretomes of E. coli and observed surprising reproducibility in positions of such rare events, assuming the functionality of ring isoforms or their permuted derivatives in bacteria.

A novel onco-cardiological mouse model of lung cancer-induced cardiac dysfunction and its application in identifying potential roles of tRNA-derived small RNAs.

An increasing body of research suggests cancer-induced cardiovascular diseases, leading to the appearance of an interdisciplinary study known as onco-cardiology. Lung cancer has the highest incidence and mortality. Cardiac dysfunction constitutes a major cause of death in lung cancer patients. However, its mechanism has not been elucidated because suitable animal models that adequately mimic clinical features are lacking. Here, we established a novel chemically induced lung cancer mouse model using benzo[a]pyrene and urethane to recapitulate the general characteristics of cardiac dysfunction caused by lung cancer, the cardiac disorders in the context of the progression of lung cancer were evaluated using echocardiographic and histological approaches. The pathological changes included myocardial ischaemia, pericarditis, cardiac pre-cachexia, and pulmonary artery hypertension. We performed sequencing to detect the tRNA-derived fragments and tRNA-derived stress-induced RNAs (tRFs/tiRNAs) expressions in mouse heart tissue. 22 upregulated and 16 downregulated tRFs/tiRNAs were identified. Subsequently, the top 10 significant results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were presented. The in vitro model was established by exposing neonatal rat cardiomyocytes and myocardial fibroblasts to lung tumour cell-conditioned medium, respectively. Western blotting revealed significant changes in cardiac failure markers (atrial natriuretic peptide and α-myosin heavy chain) and cardiac fibrosis markers (Collagen-1 and Collagen-3). Our model adequately reflects the pathological features of lung cancer-induced cardiac dysfunction. Furthermore, the altered tRF/tiRNA profiles showed great promise as novel targets for therapies. These results might pave the way for research on therapeutic targets in onco-cardiology.

Transfer RNA-derived small RNAs (tsRNAs) in gastric cancer.

Transfer RNA-derived small RNAs (tsRNAs) are newly discovered noncoding RNAs (ncRNAs). According to the specific cleavage of nucleases at different sites of tRNAs, the produced tsRNAs are divided into tRNA-derived stress-inducible RNAs (tiRNAs) and tRNA-derived fragments (tRFs). tRFs and tiRNAs have essential biological functions, such as mRNA stability regulation, translation regulation and epigenetic regulation, and play significant roles in the occurrence and development of various tumors. Although the roles of tsRNAs in some tumors have been intensively studied, their roles in gastric cancer are still rarely reported. In this review, we focus on recent advances in the generation and classification of tsRNAs, their biological functions, and their roles in gastric cancer. Sixteen articles investigating dysregulated tsRNAs in gastric cancer are summarized. The roles of 17 tsRNAs are summarized, of which 9 were upregulated and 8 were downregulated compared with controls. Aberrant regulation of tsRNAs was closely related to the main clinicopathological factors of gastric cancer, such as lymph node metastasis, Tumor-Node-Metastasis (TNM) stage, tumor size, and vascular invasion. tsRNAs participate in the progression of gastric cancer by regulating the PTEN/PI3K/AKT, MAPK, Wnt, and p53 signaling pathways. The available literature suggests the potential of using tsRNAs as clinical biomarkers for gastric cancer diagnosis and prognosis and as therapeutic targets for gastric cancer treatment.