Treatment of human gastric cancer TMK-1 cells with transcription and translation inhibitors rapidly triggered cell apoptosis. Along with cell apoptosis, the Bcl-xs level was markedly upregulated suggesting a crucial role of this protein in promoting the apoptotic process. In the presence of dexamethasone, however, cell apoptosis was greatly attenuated as demonstrated by DNA histogram shift and DNA fragmentation. Studies using the glucocorticoid receptor antagonist Rl 486 indicated that attenuation of apoptosis was mediated through glucocorticoid receptors. Dexamethasone not only suppressed the apoptosis-associated upregulation of Bcl-xs but also enhanced the basal level of BC1-XL in the cells. In addition, bcl-x mRNA stability was significantly extended in the presence of dexamethasone. These results indicate that dexamethasone exerted a protective effect and delayed apoptosis of TMK-1 cells by modulating bcl-x gene expression.
is known for its morphologic and molecular diversity. Clinically documented glioma with epithelial differentiation is rare and linked to poor prognosis with unknown mechanisms. 1,2 We identified an epigenetically modulated and stress-related glioma epithelial transcriptional program showing correlation with aggressiveness, recurrence and prognosis in glioma patients, and highlighted ΔNp63 as a likely driver of this cellular plasticity. The study flow diagram is shown in Figure S1. We applied the GENIE3 algorithm 3 to transcriptomes of 212 heterogeneous Gene Expression Omnibus brain samples with genes prefiltered by correlation (Pearson's R > 0.8) for regulatory network reconstruction. Regulons, namely regulatory relationships, were established concerning 37 core transcription factors (TFs) (top 1% most confident regulations and ≥10 targets). Based on connections among TFs (Table S1), we aggregated the regulons to eight clusters denoted C1 to C8. Nearly all these regulon clusters were univariately associated with prognosis in TCGA glioma patients (Figure S2A). However, only one regulon cluster, the C6 containing 8 TFs and 76 targets, showed independent prognostic significance after adjustment for established glioma prognosticators (Figure S2B). Markers as well as regulators for epithelial differentiation were enriched in C6 genes. We further deconvoluted C6 into two major subsets of genes (Figure S3), with the larger (n = 37) as C6a, which mainly consisted of end targets including epithelial/keratinocyte markers (e.g., cytokeratins), and the smaller (n = 18) as C6b, which mainly consisted of upstream regulators including TP63 (key regulator of basal/squamous subtype carcinoma) and MACC1 (coactivator of the receptor tyrosine kinase gene MET also involved in basal/squamous subtype carcinoma) 4 (Table S2). Higher C6b expression was found in glioblastoma (GBM) versus low grade glioma and in recurrent versus primary tumors (Figure S2C). High C6b was an independent predictor for unfavorable prognosis in glioma (Figure S2D). We developed a network-based approach to prioritize key C6 regulators using scRNA-seq data (n = 658). MET This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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