Exploring the regulatory role of tsRNAs in the TNF signaling pathway: Implications for cancer and non-cancer diseases.

Transfer RNA-derived small RNAs (tsRNAs), a recently identified subclass of small non-coding RNAs (sncRNAs), emerge through the cleavage of mature transfer RNA (tRNA) or tRNA precursors mediated by specific enzymes. The tumor necrosis factor (TNF) protein, a signaling molecule produced by activated macrophages, plays a pivotal role in systemic inflammation. Its multifaceted functions include the capacity to eliminate or hinder tumor cells, enhance the phagocytic capabilities of neutrophils, confer resistance against infections, induce fever, and prompt the production of acute phase proteins. Notably, four TNF-related tsRNAs have been conclusively linked to distinct diseases. Examples include 5'tiRNA-Gly in skeletal muscle injury, tsRNA-21109 in systemic lupus erythematosus (SLE), tRF-Leu-AAG-001 in endometriosis (EMs), and tsRNA-04002 in intervertebral disk degeneration (IDD). These tsRNAs exhibit the ability to suppress the expression of TNF-α. Additionally, KEGG analysis has identified seven tsRNAs potentially involved in modulating the TNF pathway, exerting their influence across a spectrum of non-cancerous diseases. Noteworthy instances include aberrant tiRNA-Ser-TGA-001 and tRF-Val-AAC-034 in intrauterine growth restriction (IUGR), irregular tRF-Ala-AGC-052 and tRF-Ala-TGC-027 in obesity, and deviant tiRNA-His-GTG-001, tRF-Ser-GCT-113, and tRF-Gln-TTG-035 in irritable bowel syndrome with diarrhea (IBS-D). This comprehensive review explores the biological functions and mechanisms of tsRNAs associated with the TNF signaling pathway in both cancer and other diseases, offering novel insights for future translational medical research.

Exploring the role of tRNA-derived small RNAs (tsRNAs) in disease: implications for HIF-1 pathway modulation.

The tRNA-derived small RNAs (tsRNAs) can be categorized into two main groups: tRNA-derived fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs). Each group possesses specific molecular sizes, nucleotide compositions, and distinct physiological functions. Notably, hypoxia-inducible factor-1 (HIF-1), a transcriptional activator dependent on oxygen, comprises one HIF-1ß subunit and one HIF-α subunit (HIF-1α/HIF-2α/HIF-3α). The activation of HIF-1 plays a crucial role in gene transcription, influencing key aspects of cancer biology such as angiogenesis, cell survival, glucose metabolism, and invasion. The involvement of HIF-1α activation has been demonstrated in numerous human diseases, particularly cancer, making HIF-1 an attractive target for potential disease treatments. Through a series of experiments, researchers have identified two tiRNAs that interact with the HIF-1 pathway, impacting disease development: 5'tiRNA-His-GTG in colorectal cancer (CRC) and tiRNA-Val in diabetic retinopathy (DR). Specifically, 5'tiRNA-His-GTG promotes CRC development by targeting LATS2, while tiRNA-Val inhibits Sirt1, leading to HIF-1α accumulation and promoting DR development. Clinical data have further indicated that certain tsRNAs' expression levels are associated with the prognosis and pathological features of CRC patients. In CRC tumor tissues, the expression level of 5'tiRNA-His-GTG is significantly higher compared to normal tissues, and it shows a positive correlation with tumor size. Additionally, KEGG analysis has revealed multiple tRFs involved in regulating the HIF-1 pathway, including tRF-Val-AAC-016 in diabetic foot ulcers (DFU) and tRF-1001 in pathological ocular angiogenesis. This comprehensive article reviews the biological functions and mechanisms of tsRNAs related to the HIF-1 pathway in diseases, providing a promising direction for subsequent translational medicine research.

Unveiling the role of tRNA-derived small RNAs in MAPK signaling pathway: implications for cancer and beyond.

tRNA-derived small RNAs (tsRNAs) are novel small non-coding RNAs originating from mature or precursor tRNAs (pre-tRNA), typically spanning 14 to 30 nt. The Mitogen-activated protein kinases (MAPK) pathway orchestrates cellular responses, influencing proliferation, differentiation, apoptosis, and transformation. tsRNAs influence the expression of the MAPK signaling pathway by targeting specific proteins within the pathway. Presently, four MAPK-linked tsRNAs have implications in gastric cancer (GC) and high-grade serous ovarian cancer (HGSOC). Notably, tRF-Glu-TTC-027 and tRF-Val-CAC-016 modulate MAPK-related protein expression, encompassing p38, Myc, ERK, CyclinD1, CyclinB, and c-Myc, hindering GC progression via MAPK pathway inhibition. Moreover, tRF-24-V29K9UV3IU and tRF-03357 remain unexplored in specific mechanisms. KEGG analysis posits varied tsRNAs in MAPK pathway modulation for diverse non-cancer maladies. Notably, high tRF-36-F900BY4D84KRIME and tRF-23-87R8WP9IY expression relates to varicose vein (VV) risk. Elevated tiRNA-Gly-GCC-001, tRF-Gly-GCC-012, tRF-Gly-GCC-013, and tRF-Gly-GCC-016 target spinal cord injury (SCI)-related brain-derived neurotrophic factor (BDNF), influencing MAPK expression. tRF-Gly-CCC-039 associates with diabetes foot sustained healing, while tRF-5014a inhibits autophagy-linked ATG5 in diabetic cardiomyopathy (DCM). Additionally, tsRNA-14783 influences keloid formation by regulating M2 macrophage polarization. Upregulation of tRF-Arg-ACG-007 and downregulation of tRF-Ser-GCT-008 are associated with diabetes. tsRNA-04002 alleviates Intervertebral disk degeneration (IDD) by targeting PRKCA. tsRNA-21109 alleviates Systemic lupus erythematosus (SLE) by inhibiting macrophage M1 polarization. The upregulated tiNA-Gly-GCC-002 and the downregulated tRF-Ala-AGC-010, tRF-Gln-CTG-005 and tRF-Leu-AAG-001 may be involved in the pathogenesis of Lupus nephritis (LN) by affecting the expression of MAPK pathway. Downregulation of tsRNA-1018, tsRNA-3045b, tsRNA-5021a and tsRNA-1020 affected the expression of MAPK pathway, thereby improving Acute lung injury (ALI). This review comprehensively dissects tsRNA roles in MAPK signaling across cancers and other diseases, illuminating a novel avenue for translational medical exploration.

Aggrephagy-related LncRNAs index: A predictor for HCC prognosis, immunotherapy efficacy, and chemosensitivity.

BACKGROUND: Due to the complexity and heterogeneity of hepatocellular carcinoma, the existing clinical staging criterias are insufficient to accurately reflect the tumor microenvironment and predict the prognosis of HCC patients. Aggrephagy, as a type of selective autophagy, is associated with various phenotypes of malignant tumors. OBJECTIVE: This study aimed to identify and validate a prognostic model based on aggrephagy-related LncRNAs to assess the prognosis and immunotherapeutic response of HCC patients. METHODS: Based on the TCGA-LIHC cohort, aggrephagy-related LncRNAs were identified. Univariate Cox regression analysis and lasso and multivariate Cox regression were used to construct a risk-scoring system based on eight ARLs. CIBERSORT, ssGSEA, and other algorithms were used to evaluate and present the immune landscape of tumor microenvironment. RESULTS: The high-risk group had a worse overall survival (OS) than the low-risk group. Patients in the high-risk group are more likely to benefit from immunotherapy because of their high infiltration level and high immune checkpoint expression. CONCLUSION: The ARLs signature is a powerful predictor of prognosis for HCC patients, and the nomogram based on this model can help clinicians accurately determine the prognosis of HCC patients and screen for specific subgroups of patients who are more sensitive to immunotherapy and chemotherapy.

Prognostic Value of Immune-Related lncRNA SBF2-AS1 in Diffuse Lower-Grade Glioma.

LncRNA SET-binding factor 2 (SBF2) antisense RNA1 (SBF2-AS1) has been proven to play an oncogenic role in various types of tumors, but the prognostic role of SBF2-AS1 in tumors, especially in diffuse lower-grade glioma (LGG), is still unclear. Here, we aimed to investigate the prognostic value of SBF2-AS1 in LGG. The LGG expression profiles from The Cancer Genome Atlas (TCGA, n = 524) and Chinese Glioma Genome Atlas (CGGA, n = 431) were mined by Kaplan-Meier analysis, Cox regression analysis, Chi-square test and GSEA analysis. Through Kaplan-Meier analysis, we found the prognosis of LGG patients with high expression of SBF2-AS1 were worse than that of patients with low expression (Log Rank P < 0.001). Cox analysis showed SBF2-AS1 was an independent prognostic factor for poorer overall survival in LGG (P < 0.05). SBF2-AS1 was found to be significantly related to IDH mutation status and SBF2-AS1 was highly expressed in IDH wildtype group. GSEA analysis obtained a total of 126 GO terms and 6 KEGG pathways that were significantly enriched in SBF2-AS1 high expression phenotype (NOM P value < 0.05). We found these 126 GO terms and KEGG pathways were mainly related to immunity. In conclusion, lncRNA SBF2-AS1 expression is an immune-related lncRNA associated with unfavorable overall survival in LGG. SBF2-AS1 could be a reliable prognostic biomarker for patients with LGG.

MicroRNA-193a-5p exerts a tumor suppressor role in glioblastoma via modulating NOVA1.

BACKGROUND AND OBJECTIVES: Glioblastoma (GBM) is the most common and lethal of intracranial tumors, which is characterized by extensive proliferation and the diffused invasion of tumor cells. MicroRNA-193a-5p (miR-193a-5p) have been demonstrated previously as a functional suppressor in the development and progression of various cancers. The current study aimed to investigate whether miR-193a-5p influences cell proliferation and migration through the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway by targeting neuro-oncological ventral antigen 1 (NOVA1) in glioblastoma. MATERIALS AND METHODS: The miR-193a-5p expression was detected by quantitative real-time polymerase chain reaction assay in GBM tissues and cell lines. Cell Counting Kit-8 assay, colony formation analysis, wound-healing, and transwell invasion assays were performed to evaluate cell proliferation, colony formation, migration, and invasion, respectively. Western blot analysis and luciferase reporter gene assay were performed to verify the downstream target gene of miR-193a-5p. RESULTS: The expression of miR-193a-5p was significantly downregulated in GBM tissues and cell lines. Kaplan-Meier analysis showed that patients with low miR-193a-5p expression had a shorter disease-free survival (P < 0.05). Functionally, miR-193a-5p overexpression dramatically suppressed the proliferation, colony formation, migration, and invasion in glioma cells. Bioinformatics prediction and a luciferase assay confirmed that NOVA1 was a direct functional target of miR-193a-5p. Moreover, ectopic expression of NOVA1 could partially reverse the inhibitory effects of miR-193a-5p on glioma cell proliferation, colony formation, migration, and invasion. NOVA1 overexpression abrogated the inhibitory effect of miR-193a-5p on the PTEN/PI3k/AKT pathway. CONCLUSION: Taken together, our findings suggested that miR-193a-5p functions as a tumor suppressor in glioma cells by directly targeting NOVA1.