Glioma is the most common type of central nervous system tumor. SWItch/sucrose non-fermentable (SWI/SNF) is a tumor suppressor that serves an important role in epithelial-mesenchymal transition (EMT). The present study aimed to identify key molecules involved in the EMT process. SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 2 (SMARCC2) is mutated in and its expression is low in multiple types of cancer. SMARCC2 is the core subunit of the chromatin-remodeling complex, SWI/SNF. Relative mRNA SMARCC2 expression levels in human glioma tissue were analyzed via reverse transcription-quantitative PCR, whereas the protein expression levels were determined via immunohistochemistry staining. SMARCC2 expression was knocked down in glioma cells using small interfering RNA (si) and overexpressed by infection with adenovirus vectors carrying SMARCC2 cDNA. Wound healing and Transwell assays were performed to assess cell migration and invasion, respectively. Subsequently, immunofluorescence and western blotting were performed to analyze the expression levels of the oncogene c-Myc, which is associated with SMARCC2. SMARCC2 combines with C-MYC to downregulate its expression. Consistent with the results of the bioinformatics analysis, which revealed that the upregulated expression levels of SMARCC2 were associated with a more favorable prognosis in patients with glioma, the mRNA and protein expression levels of SMARCC2 were significantly upregulated in low-grade glioma tissues compared with high-grade glioma tissues. The results of the wound healing assay demonstrated that cell migration was significantly increased in the siSMARCC2-1/3 groups compared with the negative control (NC) group. By contrast, the migratory ability of cells was significantly reduced following transduction with adenovirus overexpressing SMARCC2, which upregulated the expression of SMARCC2, compared with the lentiviral vector-non-specific control (LVS-NC) group. The Transwell assay results further showed that SMARCC2 overexpression significantly inhibited the migratory and invasive abilities of U87MG and LN229 cells compared with the LVS-NC group. Co-immunoprecipitation assays were subsequently conducted to validate the binding of SMARCC2 and c-Myc; the results demonstrated that the expression of c-Myc was downregulated in adenovirus-transfected cells compared with LVS-NC-transfected cells. The results of the western blotting experiments demonstrated that the expression levels of N-cadherin, vimentin, snail family transcriptional repressor 1 and β-catenin were notably downregulated, whereas the expression levels of T-cadherin were markedly upregulated in cell lines stably overexpressing SMARCC2 compared with the LVS-NC group. In conclusion, the results of the present study suggested that SMARCC2 may inhibit Wnt/β-catenin signaling by regulating c-Myc expression in glioma. SMARCC2 regulates the EMT status of the glioblastoma cell line by mediating the expression of the oncogene C-MYC to inhibit its migration and ...

ObjectiveThe role of m6A modification in kidney transplant-associated immunity, especially in alloimmunity, still remains unknown. This study aims to explore the potential value of m6A-related immune genes in predicting graft loss and diagnosing T cell mediated rejection (TCMR), as well as the possible role they play in renal graft dysfunction.MethodsRenal transplant-related cohorts and transcript expression data were obtained from the GEO database. First, we conducted correlation analysis in the discovery cohort to identify the m6A-related immune genes. Then, lasso regression and random forest were used respectively to build prediction models in the prognosis and diagnosis cohort, to predict graft loss and discriminate TCMR in dysfunctional renal grafts. Connectivity map (CMap) analysis was applied to identify potential therapeutic compounds for TCMR.ResultsThe prognostic prediction model effectively predicts the prognosis and survival of renal grafts with clinical indications (P< 0.001) and applies to both rejection and non-rejection situations. The diagnostic prediction model discriminates TCMR in dysfunctional renal grafts with high accuracy (area under curve = 0.891). Meanwhile, the classifier score of the diagnostic model, as a continuity index, is positively correlated with the severity of main pathological injuries of TCMR. Furthermore, it is found that METTL3, FTO, WATP, and RBM15 are likely to play a pivotal part in the regulation of immune response in TCMR. By CMap analysis, several small molecular compounds are found to be able to reverse TCMR including fenoldopam, dextromethorphan, and so on.ConclusionsTogether, our findings explore the value of m6A-related immune genes in predicting the prognosis of renal grafts and diagnosis of TCMR.

Switch/sucrose-nonfermenting (SWI/SNF) complexes play a key role in chromatin remodeling. Recent studies have found that SMARCC2, as the core subunit of the fundamental module of the complex, plays a key role in its early assembly. In this study, we found a unique function of SMARCC2 in inhibiting the progression of glioblastoma by targeting the DKK1 signaling axis. Low expression of SMARCC2 is found in malignant glioblastoma (GBM) compared with low-grade gliomas. SMARCC2 knockout promoted the proliferation of glioblastoma cells, while its overexpression showed the opposite effect. Mechanistically, SMARCC2 negatively regulates transcription by dynamically regulating the chromatin structure and closing the promoter region of the target gene DKK1, which can be bound by the transcription factor EGR1. DKK1 knockdown significantly reduced the proliferation of glioblastoma cell lines by inhibiting the PI3K–AKT pathway. We also studied the functions of the SWIRM and SANT domains of SMARCC2 and found that the SWIRM domain plays a more important role in the complete chromatin remodeling function of SMARCC2. In addition, in vivo studies confirmed that overexpression of SMARCC2 could significantly inhibit the size of intracranial gliomas in situ in nude mice. Overall, this study shows that SMARCC2, as a tumor suppressor, inhibits the proliferation of glioblastoma by targeting the transcription of the oncogene DKK1 through chromatin remodeling, indicating that SMARCC2 is a potentially attractive therapeutic target in glioblastoma.