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Exosomal hsa_circRNA_104484 and hsa_circRNA_104670 may serve as potential novel biomarkers and therapeutic targets for sepsis.

ABSTRACT: In order to explore the role of exosomal circRNAs in the occurrence and development of sepsis, we looked for potential diagnostic markers to accurately identify sepsis and to lay a molecular basis for precise treatment. Ultracentrifugation was used to extract exosomes from the serum of patients with sepsis and healthy individuals. Then, changes in circRNA expression in exosomes were studied by circRNA microarray analysis. Gene ontology (GO) analysis and Kyoto City Encyclopaedia of Genes and Genomes (KEGG) pathway analysis were used to annotate the biological functions and pathways of genes, and a circRNA-miRNA-mRNA regulatory network was constructed. In the microarray analysis, 132 circRNAs were significantly differentially expressed, including 80 and 52 that were upregulated and downregulated, respectively. RT-qPCR verified the results of microarray analysis: hsa_circRNA_104484 and hsa_circRNA_104670 were upregulated in sepsis serum exosomes. ROC analysis showed that hsa_circRNA_104484 and hsa_circRNA_104670 in serum exosomes have the potential to be used as diagnostic markers for sepsis. The circRNA-miRNA-mRNA network predicted the potential regulatory pathways of differentially expressed circRNAs. There are differences in the expression of circRNA in serum exosomes between patients with sepsis and healthy individuals, which may be involved in the occurrence and development of the disease. Among them, elevations in hsa_circRNA_104484 and hsa_circRNA_104670 could be used as novel diagnostic biomarkers and molecular therapeutic targets.

SUBMITTER: Tian C

PROVIDER: S-EPMC8266806 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAutophagy related protease 4B (ATG4B) is a protease required for autophagy processing, which is strongly implicated in cancer progression. Phosphorylation of ATG4B is crucial for activation of its protease activity. However, little is known about the relationship of ATG4B and its phosphorylated form at Ser 383 and 392 sites (pS383/392-ATG4B), with clinical outcomes, particularly in colorectal cancer (CRC).MethodsThe ATG4B gene expression in CRC patients was obtained from The Cancer Genome Atlas (TCGA) database to analyze its clinical relevance. Tissue microarrays composed of 118 CRC patient specimens were used to determine the associations of ATG4B and pS383/392-ATG4B protein levels with prognosis. The biological functions of ATG4B in CRC cells were inspected with cell proliferation, mobility and spheroid culture assays.ResultsATG4B gene expression was elevated in tumor tissues of CRC patients compared to that in adjacent normal tissues and high level of ATG4B expression was associated with poor survival. Similarly, protein levels of ATG4B and pS383/392-ATG4B were highly correlated with worse overall survival and disease-free survival. Stratification analysis results showed that high level of ATG4B had significantly higher risk of mortality in males and elderly patients compared to those female patients and patients 60 years or younger. In contrast, multivariate Cox's regression analysis indicated that high level of pS383/392-ATG4B was significantly linked to unfavorable overall survival and disease-free survival of males and elderly patients, whereas, it had no correlation with female patients and patients 60 years or younger. Moreover, high level of ATG4B was positively associated with increased mortality risk in patients with advanced AJCC stages (III and IV) and lymph node invasion (N1 and N2) for both overall survival and disease-free survival. Nevertheless, high level of pS383/392-ATG4B was positively correlated with increased mortality risk in patients with early AJCC stages (I and II) and without lymph node invasion (N0). In addition, silencing ATG4B attenuated migration, invasion, and further enhanced the cytotoxic effects of chemotherapeutic drugs in two and three-dimensional cultures of CRC cells.ConclusionsOur results suggest that ATG4B and pS383/392-ATG4B might be suitable biomarkers and therapeutic targets for CRC.

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Exosomal hsa_circRNA_104484 and hsa_circRNA_104670 may serve as potential novel biomarkers and therapeutic targets for sepsis.

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