High malignancy and early metastasis are the hallmarks of hepatocellular carcinoma (HCC). Here, we report that Cezanne2 expression is downregulated in HCC cells and in HCC patients' tumorous tissues and that Cezanne2 is inversely associated with Snail1 expression in HCC patients' tumorous tissues. Chromatin immunoprecipitation assays and the reporter gene assay showed that Snail1 binds to the promoter of the Cezanne2 gene and mediates the direct consequence of Cezanne2 repression. Enhanced expression of Cezanne2 could suppress proliferation, migration and invasion in HCC cells. Further, Cezanne2 could regulate MMP (matrix metalloproteinase)2, MMP9 and ICAM1 (intercellular adhesion molecule) levels through modulation of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cell) signaling cascade. Co-immunoprecipitation and in vivo deubiquitination assay indicated that Cezanne2 interacts with TNF receptor-associated factor (TRAF)6 and cleaves the polyubiquitin from TRAF6 substrates. Our data reveal that Snail1-mediated suppression of Cezanne2 may have a key role in HCC malignancy.
Glutathione synthetase deficiency (GSSD) is a rare inborn error of glutathione metabolism with autosomal recessive inheritance. The severe form of the disease is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. A case of a male newborn infant who had severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia is reported. A high level of 5-oxoproline was detected in his urine and a diagnosis of generalized GSSD was made. DNA sequence analysis revealed the infant to be compound heterozygous with two mutations, c.738dupG in exon 8 of GSS gene resulting in p.S247fs and a repetitive sequence in exon 3 of GSS gene. Treatment after diagnosis of GSSD included supplementation with antioxidants and oral sodium hydrogen bicarbonate. However, he maintained a variable degree of metabolic acidosis and succumbed shortly after his parents requested discontinuation of therapy because of dismal prognosis and medical futility when he was 18 days old.
The interleukin-12B (IL12B) gene encodes the p40 chain of IL-12, a pro-inflammatory cytokine that antagonizes Th2 phenotype and, hence, may have a critical role in the pathogenesis of allergic asthma. In this report, we describe the identification of a novel IL12B promoter polymorphism (T-to-A exchange) at position À 536. The IL12B À 536AA genotype was significantly associated with asthma in the Chinese populations (P ¼ 0.011, odds ratio ¼ 2.227). The risk-associated A allele was linked to reduced expression of IL12B mRNA levels and IL12B production in asthmatic patients. Luciferase reporter assay provided evidence that risk-associated A allele reduced the promoter activity of IL12B gene compared with those of the promoter containing the protective T allele. We further observed that decreasing binding effects between the risk alleles A of IL12B and CCAAT/enhancer binding protein alpha (C/EBPa) through A allele sequence mediated streptavidin-conjugated agarose pulldown and biotin-labelled A allele mediated electrophoretic mobility shift assay. We also observed additive effects of the risk alleles of IL12B and decreased mRNA levels of C/EBPa in asthmatic patients. Therefore, we postulated that the presence of À 536A allele in IL12B promoter could predispose to the development of allergic asthma.
BackgroundPituitary neuroendocrine tumors (PitNETs), which originate from the pituitary gland, account for 10%–15% of all intracranial neoplasms. Recent studies have indicated that enhancer RNAs (eRNAs) exert regulatory effects on tumor growth. However, the mechanisms underlying the eRNA-mediated tumorigenesis of PitNETs have not been elucidated.MethodsNormal pituitary and PitNETs tissues were used to identify the differentially expressed eRNAs (DEEs). Immune gene sets and hallmarks of cancer gene sets were quantified based on single sample gene set enrichment analysis (ssGSEA) algorithm using GSVA. The perspective of immune cells among all samples was calculated by the CIBERSORT algorithm. Moreover, the regulatory network composed of key DEEs, target genes of eRNAs, hallmarks of cancer gene sets, differentially expressed TF, immune cells and immune gene sets were constructed by Pearson correlation analysis. Small molecular anti-PitNETs drugs were explored by CMap analysis and the accuracy of the study was verified by in vitro and in vivo experiments, ATAC-seq and ChIP-seq.ResultsIn this study, data of 134 PitNETs and 107 non-tumorous pituitary samples were retrieved from a public database to identify differentially expressed genes. In total, 1128 differentially expressed eRNAs (DEEs) (494 upregulated eRNAs and 634 downregulated eRNAs) were identified. Next, the correlation of DEEs with cancer-related and immune-related gene signatures was examined to establish a co-expression regulatory network comprising 18 DEEs, 50 potential target genes of DEEs, 5 cancer hallmark gene sets, 2 differentially expressed transcription factors, 4 immune cell types, and 4 immune gene sets. Based on this network, the following four therapeutics for PitNETs were identified using Connectivity Map analysis: ciclopirox, bepridil, clomipramine, and alexidine. The growth-inhibitory effects of these therapeutics were validated using in vitro experiments. Ciclopirox exerted potential growth-inhibitory effects on PitNETs. Among the DEEs, GNLY, HOXB7, MRPL33, PRDM16, TCF7, and ZNF26 were determined to be potential diagnostic and therapeutic biomarkers for PitNETs.ConclusionThis study illustrated the significant influence of eRNAs on the occurrence and development of PitNETs. By constructing the co-expression regulation network, GNLY, HOXB6, MRPL33, PRDM16, TCF7, and ZNF26 were identified as relatively significant DEEs which were considered as the novel biomarkers of diagnosis and treatment of PitNETs. This study demonstrated the roles of eRNAs in the occurrence and development of PitNETs and revealed that ciclopirox was a potential therapeutic for pituitary adenomas.
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