Catabolic control protein (CcpA) is linked to complex carbohydrate utilization and virulence factor in many bacteria species, influences the transcription of target genes by many mechanisms. To characterize the activity and regulatory mechanisms of CcpA in Streptococcus sanguinis, here, we analyzed the transcriptome of Streptococcus sanguinis SK36 and its CcpA-null derivative (ΔCcpA) using RNA-seq. Compared to the regulon of CcpA in SK36 in the RegPrecise database, we found that only minority of differentially expressed genes (DEGs) contained putative catabolite response element (cre) in their regulatory regions, indicating that many genes could have been affected indirectly by the loss of CcpA and analyzing the sequence of the promoter region using prediction tools is not a desirable method to recognize potential target genes of global regulator CcpA. Gene ontology and pathway analysis of DEGs revealed that CcpA exerts an influence predominantly involved in carbon catabolite metabolism and some amino acid catabolite pathways, which has been linked to expression of virulence genes in many pathogens and coordinately regulate the disease progression in vivo studies. However, in some scenarios, differences observed at the transcript level could not reflect the real differences at the protein level. Therefore, to confirm the differences in phenotype and virulence of SK36 and ΔCcpA, we characterized the role of CcpA in the regulation of biofilm development, EPS production and the virulence of Streptococcus sanguinis. Results showed CcpA inactivation impaired biofilm and EPS formation, and CcpA also involved in virulence in rabbit infective endocarditis model. These findings will undoubtedly contribute to investigate the mechanistic links between the global regulator CcpA and the virulence of Streptococcus sanguinis, further broaden our understanding of the relationship between basic metabolic processes and virulence.
Background: Glioma is the most common malignant tumor of the central nervous system, with high heterogeneity, strong invasiveness, high therapeutic resistance, and poor prognosis, comprehending a serious challenge in neuro-oncology. Until now, the mechanisms underlying glioma progression have not been fully elucidated.
Methods:The expression of DExH-box helicase 9 (DHX9) in tissues and cells was detected by qRT-PCR and western blot. EdU and transwell assays were conducted to assess the effect of DHX9 on proliferation, migration and invasion of glioma cells.Cocultured model was used to evaluate the role of DHX9 on macrophages recruitment and polarization. Animal study was performed to explore the role of DHX9 on macrophages recruitment and polarization in vivo. Bioinformatics analysis, dualluciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay was used to explore the relation between DHX9 and TCF12/CSF1.Results: DHX9 was elevated in gliomas, especially in glioblastoma multiforme (GBM).Besides promoting the proliferation, migration, and invasion of glioma cells, DHX9 facilitated the infiltration of macrophages into glioma tissues and polarization to M2-like macrophages, known as tumor-associated macrophages (TAMs). DHX9 silencing decreased the expression of colony-stimulating factor 1 (CSF1), which partially restored the inhibitory effect on malignant progress of glioma and infiltration of TAMs caused by DHX9 knockdown by targeting the transcription factor 12 (TCF12). Moreover, TCF12 could directly bind to the promoter region of CSF1.
Conclusion: DHX9/TCF12/CSF1 axis regulated the increases in the infiltration ofTAMs to promote glioma progression and might be a novel potential target for future immune therapies against gliomas.
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