Dataset Information

Downregulation of hsa_circ_0001836 Induces Pyroptosis Cell Death in Glioma Cells via Epigenetically Upregulating NLRP1.

ABSTRACT:

Background

It has been shown that circular RNAs (circRNAs) play a vital role in the progression of glioma. Recently, hsa_circ_0001836 was found to be upregulated in glioma tissues, but the role of hsa_circ_0001836 in glioma remains unclear.

Methods

EdU staining and flow cytometry assays were used to measure the viability and death of glioma cells. In addition, scanning electron microscopy (SEM) was used to observe the morphology of cells undergoing cell death.

Results

Hsa_circ_0001836 expression was upregulated in U251MG and SHG-44 cells. In addition, hsa_circ_0001836 knockdown significantly reduced the viability and proliferation of U251MG and SHG-44 cells. Moreover, hsa_circ_0001836 knockdown markedly induced the pyroptosis of U251MG and SHG-44 cells, evidenced by the increased expressions of NLRP1, cleaved caspase 1 and GSDMD-N. Meanwhile, methylation specific PCR (MSP) results indicated that hsa_circ_0001836 knockdown epigenetically increased NLRP1 expression via mediating DNA demethylation of NLRP1 promoter region. Furthermore, downregulation of hsa_circ_0001836 notably induced pyroptosis and inhibited tumor growth in a mouse xenograft model of glioma.

Conclusion

Collectively, hsa_circ_0001836 knockdown could induce pyroptosis cell death in glioma cells in vitro and in vivo via epigenetically upregulating NLRP1 expression. These findings suggested that hsa_circ_0001836 may serve as a potential therapeutic target for the treatment of glioma.

SUBMITTER: Liu Y

PROVIDER: S-EPMC8044449 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposeNeuronal pyroptosis is a type of regulated cell death triggered by proinflammatory signals. CCR5 (C-C chemokine receptor 5)-mediated inflammation is involved in the pathology of various neurological diseases. This study investigated the impact of CCR5 activation on neuronal pyroptosis and the underlying mechanism involving cAMP-dependent PKA (protein kinase A)/CREB (cAMP response element binding)/NLRP1 (nucleotide-binding domain leucine-rich repeat pyrin domain containing 1) pathway after experimental intracerebral hemorrhage (ICH).MethodsA total of 194 adult male CD1 mice were used. ICH was induced by autologous whole blood injection. Maraviroc (MVC)-a selective antagonist of CCR5-was administered intranasally 1 hour after ICH. To elucidate the underlying mechanism, a specific CREB inhibitor, 666-15, was administered intracerebroventricularly before MVC administration in ICH mice. In a set of naive mice, rCCL5 (recombinant chemokine ligand 5) and selective PKA activator, 8-Bromo-cAMP, were administered intracerebroventricularly. Short- and long-term neurobehavioral assessments, Western blot, Fluoro-Jade C, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and immunofluorescence staining were performed.ResultsThe brain expression of CCL5 (chemokine ligand 5), CCR5, PKA-Cα (protein kinase A-Cα), p-CREB (phospho-cAMP response element binding), and NLRP1 was increased, peaking at 24 hours after ICH. CCR5 was expressed on neurons, microglia, and astrocytes. MVC improved the short- and long-term neurobehavioral deficits and decreased neuronal pyroptosis in ipsilateral brain tissues at 24 hours after ICH, which were accompanied by increased PKA-Cα and p-CREB expression, and decreased expression of NLRP1, ASC (apoptosis-associated speck-like protein containing a CARD), C-caspase-1, GSDMD (gasdermin D), and IL (interleukin)-1β/IL-18. Such effects of MVC were abolished by 666-15. At 24 hours after injection in naive mice, rCCL5 induced neurological deficits, decreased PKA-Cα and p-CREB expression in the brain, and upregulated NLRP1, ASC, C-caspase-1, N-GSDMD, and IL-1β/IL-18 expression. Those effects of rCCL5 were reversed by 8-Bromo-cAMP.ConclusionsCCR5 activation promoted neuronal pyroptosis and neurological deficits after ICH in mice, partially through the CCR5/PKA/CREB/NLRP1 signaling pathway. CCR5 inhibition with MVC may provide a promising therapeutic approach in managing patients with ICH.