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Overview of distinct 8-Oxoguanine profiles of messenger RNA in normal and senescent cancer cells

ABSTRACT: Background: Cellular senescence plays a key role in the development of cancer, but the underlying mechanisms are unknown.Recently, several recent studies have shown that RNA methylation is closely related to cancer cell aging. 8-Oxoguanine (o8G) is an important and widely distributed methylation modification whose role in cancer cell senescence is far from elucidated. Methods: In this study, senescent cancer cell models (CaCO2 cells) were constructed by knocking down the ADAR1 gene. RNA immunoprecipitation sequencing was used to identify the o 8 G peaks on messenger RNA (mRNA) of normal CaCO2 cells and senescent CaCO2 cells, and the distribution characteristics of mRNA o 8 G modification were identified. Further bioinformatics analysis of the sequencing data was performed to preliminarily elucidate the potential function of the o8G-modified mRNA. Results: There were significant differences in mRNA o 8 G modification distribution between normal and senescent CaCO2 cells.It is suggested that o8G modification may play a key role in inducing cancer cells or promoting cancer cell senescence. Gene ontology (GO) enrichment analysis showed that the genes modified by o 8 G were enriched in Cellular component organization or biogenesis, Focal adhesion,and RNA binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the genes modified by o8G areconcentrated in Focal adhesion signaling pathway, Small cell lung cancer signaling pathway and Proteoglycans in cancer signaling pathway. Conclusion: This study preliminarily revealed the different distribution patterns of o8G modification between normal CaCO2 cells and senescent CaCO2 cells. Our study established the link between o 8 G modification and cancer cell senescence, which provides a new insight into the mechanism of cancer cell senescence and a potential therapeutic target for subsequent cancer treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284992 | GEO | 2024/12/21

REPOSITORIES: GEO

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Project description:BACKGROUND: Periodontal ligament mesenchymal stem cells (PDLSCs) are a promising cell resource for cell-based regenerative medicine in dentistry. PDLSCs inevitably acquire a senescent phenotype after prolonged in vitro expansion, and the key regulators of cells during replicative senescence remain unclear.METHODS: We cultured periodontal ligament stem cells to passages 4, 10 and 20 (P4, P10, P20). The senescent phenotypes, proliferation and migration ability of PDLSCs (P4, P10, P20) were detected, and non-targeted metabonomic sequencing was performed. We treated PDLSCs with AICAR and detected the expression of FOXO1, FOXO3a, FOXO6 and AMPK phosphorylation (p-AMPK) levels of replicating senescent PDLSCs to explore the correlation between the metabolic changes and the AMPK pathway.RESULTS: Immunofluorescence staining of γ-H2AX, β-galactosidase staining, cell scratch test and qPCR were performed to confirm the occurrence of replicative senescence in PDLSCs during passaging. Three groups of cells at passage 4 (P4), passage 10 (P10) and passage 20 (P20) were collected for non-targeted metabolomics analysis. Metabonomic sequencing showed that the metabolism of replicative senescence in PDLSCs varied significantly. In particular, the content of fatty acid metabolites decreased with senescence, including capric acid, stearic acid, myristic acid and dodecanoic acid. KEGG pathway analysis showed that the AMPK signaling pathway was closely related to AMP levels. The AMP:ATP ratio increased in senescent PDLSCs; however, the levels of p-AMPK and the profile of FOXO1 and FOXO3a, which are downstream of the AMPK signaling pathway, decreased with senescence. We treated PDLSCs with AICAR, an activator of the AMPK pathway, and the phosphorylated AMPK level at P20 PDLSCs was partially restored. CONCLUSION: In summary, our study suggests that the metabolic process of PDLSCs is active in the early stage of senescence, prefers to consume fatty acids, and is attenuated in the later stages of senescence. AMP accumulates in replicative senescent PDLSCs; however, the sensitivity of AMPK phosphorylation sites is impaired, causing senescent PDLSCs to fail to respond to changes in energy metabolism. Our findings provide a new basis for the clinical application of periodontal ligament stem cells.

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Overview of distinct 8-Oxoguanine profiles of messenger RNA in normal and senescent cancer cells

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