• AIMP
• Aminoacyl tRNA synthetase
• Cancer
• Epitranscriptome
• tRF/tDR
• tRNA

• Humans
• RNA, Transfer/genetics
• RNA, Transfer/metabolism
• Carcinogenesis/genetics
• Amino Acyl-tRNA Synthetases/genetics
• Amino Acyl-tRNA Synthetases/metabolism
• Transcriptome
• Epigenesis, Genetic
• Neoplasms/genetics
• Neoplasms/metabolism
• Animals

• Bioinformatics
• Biomarkers
• Cancer
• Genomics
• tRNA halves
• tRNA-derived fragments

• Humans
• RNA, Transfer/genetics
• RNA, Transfer/metabolism
• Neoplasms/diagnosis
• Neoplasms/genetics
• Neoplasms/metabolism
• High-Throughput Nucleotide Sequencing

• cancer
• tRNA modifications
• tRNA-derived fragments
• tRNAs
• translational regulation

• 8200112759 National Natural Science Foundation of China
• 82073211 National Natural Science Foundation of China
• 82002434 National Natural Science Foundation of China
• 82003106 National Natural Science Foundation of China

• YRNA
• cancer
• midsize noncoding RNA
• noncoding RNA
• scaRNA
• snRNA
• snoRNA
• tRNA

Lung cancer, one of the most malignant tumors, has extremely high morbidity and mortality, posing a serious threat to global health. It is an urgent need to fully understand the pathogenesis of lung cancer and provide new ideas for its treatment. Interestingly, accumulating evidence has identified that transfer RNAs (tRNAs) and tRNA metabolism–associated enzymes not only participate in the protein translation but also play an important role in the occurrence and development of lung cancer. In this review, we summarize the different aspects of tRNA metabolism in lung cancer, such as tRNA transcription and mutation, tRNA molecules and derivatives, tRNA-modifying enzymes, and aminoacyl-tRNA synthetases (ARSs), aiming at a better understanding of the pathogenesis of lung cancer and providing new therapeutic strategies for it.

• lung cancer
• pathogenesis
• tRNA aminoacylation
• tRNA derivatives
• tRNA modifications
• therapeutics

• cancer marker
• extracellular vesicles
• hypopharyngeal cancer
• lung metastasis
• tRNA-derived fragment

The present study is aimed at providing systematic insight into the composition and expression of transfer RNA (tRNA) derivative transcription in high-grade serous ovarian cancer (HGSOC).

tRNA derivative expression profiles in three pairs of HGSOC and adjacent normal ovarian tissues were conducted by tRNA-derived small RNA fragment (tRF) and tRNA half (tiRNA) sequencing. The differentially expressed tRFs and tiRNAs between HGSOC and paired adjacent normal samples were screened. The targeted genes of differentially expressed tRFs and tiRNAs were screened. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) of target genes of tRFs and tiRNAs were analyzed.

There are a total of 20 significantly upregulated and 15 significantly downregulated tRFs and tiRNAs between the cancer group and the paracarcinoma group. The upregulated tRFs and tiRNAs are mucin-type O-glycan biosynthesis, glycosphingolipid biosynthesis, the glucagon signaling pathway, the AMPK signaling pathway, maturity-onset diabetes of the young, glycosphingolipid biosynthesis, the insulin signaling pathway, insulin resistance, leukocyte transendothelial migration, starch, and sucrose metabolism. The downregulated tRFs and tiRNAs are other glycan degradation, vitamin digestion and absorption, fatty acid elongation, and biosynthesis of unsaturated fatty acids.

There are significantly expressed tRFs and tiRNAs in HGSOC tissues, and these may provide potential diagnostic biomarkers and therapeutic targets for HGSOC.

Bladder cancer (BlCa) management relies on lifelong surveillance strategies with invasive interventions that adversely affect patients’ quality-of-life and lead to a high economic burden for healthcare systems. Exploitation of bladder tumors’ molecular background could lead to modern precision medicine. tRNA-derived fragments (tRFs), rather than degradation debris, are novel functional small ncRNAs that have emerged as key regulators of cellular homeostasis. This is the first study of the clinical utility of tRFs in BlCa. Using in silico analysis of the TCGA-BLCA project, we identified 5′-tRF-LysCTT (5′-tRF of tRNA^LysCTT) to be significantly deregulated in BlCa, and we have studied its clinical value in our cohort of 230 BlCa patients. Elevated 5′-tRF-LysCTT levels were significantly associated with aggressive tumor phenotype as well as early disease progression and poor treatment outcome. Integration of 5′-tRF-LysCTT with established disease markers resulted in superior prediction of patients’ prognosis, supporting personalized treatment and monitoring decisions.

The heterogeneity of bladder cancer (BlCa) prognosis and treatment outcome requires the elucidation of tumors’ molecular background towards personalized patients’ management. tRNA-derived fragments (tRFs), although originally considered as degradation debris, represent a novel class of powerful regulatory non-coding RNAs. In silico analysis of the TCGA-BLCA project highlighted 5′-tRF-LysCTT to be significantly deregulated in bladder tumors, and 5′-tRF-LysCTT levels were further quantified in our screening cohort of 230 BlCa patients. Recurrence and progression for non-muscle invasive (NMIBC) patients, as well as progression and patient’s death for muscle-invasive (MIBC) patients, were used as clinical endpoint events. TCGA-BLCA were used as validation cohort. Bootstrap analysis was performed for internal validation and the clinical net benefit of 5′-tRF-LysCTT on disease prognosis was assessed by decision curve analysis. Elevated 5′-tRF-LysCTT was associated with unfavorable disease features, and significant higher risk for early progression (multivariate Cox: HR = 2.368; p = 0.033) and poor survival (multivariate Cox: HR = 2.151; p = 0.032) of NMIBC and MIBC patients, respectively. Multivariate models integrating 5′-tRF-LysCTT with disease established markers resulted in superior risk-stratification specificity and positive prediction of patients’ progression. In conclusion, increased 5′-tRF-LysCTT levels were strongly associated with adverse disease outcome and improved BlCa patients’ prognostication.

• 5′-tRFs
• bladder cancer
• bladder tumors
• bladder urothelial carcinoma
• ncRNAs
• non coding RNAs
• tRNA fragments
• tRNA-Lys-CTT
• tRNA-derived fragments
• tRNALysCTT

The profiles of miRNAs, tRNA-derived fragments and tRNAs from lung cancer biopsy specimens indicate involvement of gene networks that modulate signaling and translation initiation. The current study highlights the important role of several regulatory small non-coding RNAs in aberrant signaling and translation deregulation in lung cancer.

Transcriptomics profiles of miRNAs, tRNAs or tRFs are used as biomarkers, after separate examination of several cancer cell lines, blood samples or biopsies. However, the possible contribution of all three profiles on oncogenic signaling and translation as a net regulatory effect, is under investigation. The present analysis of miRNAs and tRFs from lung cancer biopsies indicated putative targets, which belong to gene networks involved in cell proliferation, transcription and translation regulation. In addition, we observed differential expression of specific tRNAs along with several tRNA-related genes with possible involvement in carcinogenesis. Transfection of lung adenocarcinoma cells with two identified tRFs and subsequent NGS analysis indicated gene targets that mediate signaling and translation regulation. Broader analysis of all major signaling and translation factors in several biopsy specimens revealed a crosstalk between the PI3K/AKT and MAPK pathways and downstream activation of eIF4E and eEF2. Subsequent polysome profile analysis and 48S pre-initiation reconstitution experiments showed increased global translation rates and indicated that aberrant expression patterns of translation initiation factors could contribute to elevated protein synthesis. Overall, our results outline the modulatory effects that possibly correlate the expression of important regulatory non-coding RNAs with aberrant signaling and translation deregulation in lung cancer.

• lung cancer
• miRNAs
• signaling
• tRFs
• tRNAs
• translation

• Cigarette smokers
• E-cig users
• Exosomes
• Extracellular vesicles
• Plasma
• Waterpipe smokers
• microRNA

• Biomarkers/blood
• Case-Control Studies
• Electronic Nicotine Delivery Systems/statistics & numerical data
• Exosomes/genetics
• Gene Expression Profiling
• Gene Expression Regulation
• Gene Regulatory Networks
• Humans
• MicroRNAs/blood
• MicroRNAs/genetics
• ROC Curve
• Smokers/statistics & numerical data
• Tobacco Smoking/genetics
• Water Pipe Smoking/genetics

• R01 HL085613 NHLBI NIH HHS
• U54 CA228110 NCI NIH HHS
• 1 R01 HL135613 NIH HHS
• FDA Center for Tobacco Products & National Cancer Institute of the NIH
• National Institutes of Health

• cancer
• circRNAs
• lncRNAs
• miRNAs
• p53
• p63
• p73

Vestigial like family member 3 (VGLL3) is associated with the prognosis of epithelial ovarian cancer and soft tissue sarcoma, but its role in gastric cancer (GC) is unclear.

To explore the expression pattern and clinical significance of VGLL3 in GC.

Integrative analysis was performed on the GC transcriptome profiles and survival information deposited in the ONCOMINE, GEPIA, and ONCOLNC databases. The expression levels of VGLL3 mRNA and protein were analyzed in the freshly resected tumor and normal gastric tissues from GC patients by quantitative RT-PCR and Western blot, respectively. In addition, the in situ expression of VGLL3 in the GC tissues was determined by immunohistochemistry (IHC), and the patients were accordingly classified into the high and low expression groups. The correlation of VGLL3 expression status with patient prognosis was then determined by univariate and multivariate Cox regression analyses.

Analysis of the ONCOMINE and GEPIA databases showed that VGLL3 was significantly up-regulated in GC tissues (P = 0.003), and associated with the tumor TNM stage (P = 0.0163). The high VGLL3 expression group had a significantly worse prognosis compared to the low expression group, as per both GEPIA (P = 0.0057) and ONCOLNC (P = 0.01). The bioinformatics results were validated by the significantly higher VGLL3 mRNA and protein levels in the GC tissues compared to the adjacent normal tissues (P < 0.001) in a cohort of 30 GC patients. Furthermore, high in situ expression of VGLL3 protein was associated with more advanced N and TNM stages and HER2 mutation (P < 0.05) in a cohort of 172 patients. Kaplan-Meier analysis showed that the high VGLL3 expression group had a worse prognosis compared to the low expression group (P = 0.019). Multivariate analysis showed that VGLL3 expression status was an independent risk factor for prognosis. In addition, the prognostic risk model nomogram showed that VGLL3 was the most important indicator, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.613 for 3-year survival and 0.706 for 5-year survival. Finally, the protein interaction network analysis revealed that VGLL3 is likely involved in the Hippo signaling pathway.

VGLL3 is overexpressed in GC tissues and associated with a poor prognosis, indicating its potential as a novel prognosis biomarker and therapeutic target for GC.

• Vestigial like family member 3
• Stomach adenocarcinoma
• HER2 mutation
• Gastric cancer
• Bioinformatics analysis

• cancer
• codon usage
• drug resistance
• protein synthesis errors
• tRNAs