Search

Background. Cancer affects millions of people each year and imposes a huge economic and social burden worldwide. Cuproptosis is a recently discovered novel mode of cell death. The exact function of the cuproptosis-related gene dihydrolipoamide dehydrogenase (DLD) and its role in pan-cancer is unknown. Methods. Data were retrieved from the GTEx, TCGA, and multiple online websites. These data were used to assess the expression, prognosis, and diagnostic value of DLD in various tumors. The relationship of DLD with immune microenvironment immunomodulators, immune checkpoints, tumor mutational load (TMB), microsatellite instability (MSI), and oncology drug sensitivity was explored by correlation analysis. Results. The mRNA and protein expression of DLD differs in most cancers. Survival analysis showed that DLD was associated with prognosis with KIRC, KIRP, KICH, and UCS. DLD had a strong diagnostic value in KIRC, GBM, PAAD, and LGG (AUC > 0.9). DLD promoter methylation affects the aberrant expression of LIHC, LUSC, PAAD, READ, and THCA. DLD was negatively correlated with stromal score, immune score, and ESTIMATE score in UCEC, TGCT, LUSC, and SARC. In UCS, resting memory CD4 T cells and activated NK cells were significantly correlated with DLD expression. Significant correlations were also observed between DLD expression and immunomodulators, immune checkpoints, TMB, and MSI in various cancers. Importantly, we also identified a number of potential drugs that may target DLD. Conclusion. DLD expression is associated with a variety of tumor prognoses and plays an integral role in tumorigenesis, tumor metabolism, and immunity. [ABSTRACT FROM AUTHOR]

Objectives: Cag A+Helicobacter pylori chronic infection cause malignant transformation of the human gastric mucosa. N6-methyladenosine (m6A) modifications are the most common and abundant mRNA modifications and one of the pathways affecting tumorigenicity and tumor progression. However, the role of m6A modification in the process of chronic H. pylori infection leading to malignant transformation of gastric mucosa is unclear. Methods: In this study, we used Cag A− and Cag A+H. pylori chronic infection to establish cellular models in GES-1 cells and analyzed the cellular morphology, proliferation, apoptosis, invasiveness and tumorigenicity of gastric mucosal epithelial cells. The m6A expression levels of GES-1 cells after chronic infection with Cag A− and Cag A+H. pylori were examined, and modifying effect of FTO (the fat mass and obesity-associated protein) on CD44 was verified by MeRIP–qPCR. Finally, the FTO expression changes and m6A expression levels were further validated in clinical gastric cancer tissues. Results: Chronic Cag A+H. pylori-infected GES-1 cells exhibit altered cell morphology, apoptosis inhibition, abnormal proliferation, enhanced migration, colony formation, and increased stem cell-like properties. Meanwhile, FTO and CD44 expression was enhanced, and FTO may induce malignant transformation of gastric mucosa by regulating CD44 mRNA m6A methylation modifications. Conclusions: We verified the effect of chronic stimulation of Cag A+H. pylori on malignant transformation of gastric mucosal epithelium. revealing the possibility of FTO in promoting malignant transformation of gastric mucosa by modifying CD44 mRNA methylation, suggesting that FTO expression is a potential molecule for malignant transformation of gastric mucosal epithelial cells. [ABSTRACT FROM AUTHOR]

The present study aimed to explore the effects of Helicobacter pylori (H. pylori) infection on the expression of transcription factor GATA binding protein 3 (GATA-3) and connexin 32 (Cx32) in cultured gastric mucosa cells, and their association with each other. GES-1 cells were co-cultured with East Asian type cytotoxin-associated gene A+ H. pylori in the H. pylori group, and without H. pylori culture in the control group. Additionally, Mongolian gerbils were gavaged with H. pylori, and later the gastric antrum tissues were collected. The GATA-3 and Cx32 mRNA and protein expression levels were detected by a reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The scratch labeling fluorescent dye tracer (SLDT) technique was used to detect the gap junctional intercellular communication (GJIC) function. GATA-3 small interfering RNA (siRNA) was transfected into BGC823 cells and its effect on Cx32 expression levels was detected. The impact of GATA-3 on Cx32 promoter transcriptional activity was detected using a dual luciferase reporter assay. The results revealed that H. pylori infection increased GATA-3 expression and decreased Cx32 expression in GES-1 cells and in animal gastric tissues compared with their respective controls, whilst in BGC823 cells, GATA-3 siRNA increased Cx32 expression compared with the control. In the SLDT experiment of GES-1 cells with H. pylori infection, the fluorescent dye was primarily limited to a single cell row close to the scratch, and only a limited amount of dye passing to the second cell row, indicating that the GJIC function was substantially reduced or absent compared with the control group, where the fluorescence dye transferred to the neighboring cells of 3-4 rows, indicating a stronger GJIC function comparatively. GATA-3 inhibited the expression of the luciferase reporter gene, compared with the controls, suggesting that GATA-3 inhibited the expression of Cx32 by binding to Cx32 promoter sites. These results indicated that H. pylori-increased GATA-3 expression, which downregulated Cx32 expression, may serve an important function in gastric carcinogenesis, and GATA-3 siRNA may serve a function in the prevention and treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

Objective. CagA+/vacAs1+/vacAm1+ Helicobacter pylori upregulates the expression of tumor necrosis factor receptor–associated factor 1 (TRAF1), tumor necrosis factor receptor superfamily member 9 (4-1BB), and B-cell lymphoma-extra large (Bcl-xL) in human gastric epithelial cells. We investigated the correlation between cagA/vacAs1/vacAm1 and TRAF1/4-1BB/Bcl-xL expression in gastric mucosal tissue of patients with gastric disorders. Methods. We collected gastric mucosa samples from 35 chronic, nonatrophic gastritis (CG) patients, 41 atrophic gastritis patients, 44 intestinal metaplasia with atypical hyperplasia (IM) patients, and 28 gastric carcinoma (Ca) patients. The expression of  TRAF1, 4-1BB, and Bcl-xL was determined using western blotting. The expression of cagA, vacAs1, and vacAm1 in H. pylori was examined with polymerase chain reaction. Results. The expression of TRAF1, 4-1BB, and Bcl-xL was significantly upregulated in IM and Ca patients (P<0.05 compared with CG). There were more cases of cagA+/vacAs1+/vacAm1+ H. pylori infection in samples with elevated TRAF1, 4-1BB, or Bcl-xL expression (P<0.05). Additionally, there were a remarkably large number of samples with upregulated TRAF1/4-1BB/Bcl-xL expression in cases of cagA+/vacAs1+/vacAm1+ H. pylori infection (44 cases, 67.7%; P<0.05). Conclusions. The pathogenesis of IM and Ca may be promoted by cagA+/vacAs1+/vacAm1+ H. pylori, possibly via upregulated TRAF1, 4-1BB, and Bcl-xL in gastric mucosal tissue. [ABSTRACT FROM AUTHOR]