The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells

Cancer-associated fibroblasts (CAFs) are pivotal in tumor progression. TP53-deficiency in cancer cells is associated with robust stromal activation. The apelin-apelin receptor (APJ) system has been implicated in suppressing fibroblast-to-myofibroblast transition in non-neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin-APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53-wild colon cancer, HCT116, and Caco-2; TP53-mutant colon cancer, SW480, and DLD-1; and colon fibroblasts, CCD-18Co), resected human tissue samples of colorectal cancers, and immune-deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co-cultured with p53-suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJ-suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast-like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma- and Mad-related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ-suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR-5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell-derived exosomes induced CAF-like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.Saiki H., Hayashi Y., Yoshii S., et al. The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells. International Journal of Oncology 63, 139 (2023); https://doi.org/10.3892/ijo.2023.5587

Effects of febuxostat and allopurinol on the inflammation and cardiac function in chronic heart failure patients with hyperuricemia

Background: An elevated uric acid (UA) level is associated with an increased risk of adverse outcomes in patients with chronic heart failure (CHF). Febuxostat and allopurinol lower the UA levels and attenuate the expression of an inflammatory marker, monocyte chemoattractant protein (MCP)-1. However, a direct comparison of the effects of febuxostat and allopurinol on the inflammation and cardiac function in CHF patients with hyperuricemia has not yet been performed. Methods: A total of 61 CHF patients with hyperuricemia who had a mean left ventricular ejection fraction (LVEF) of 37.1 ± 6.7% were randomly assigned to receive febuxostat (n = 31) or allopurinol (n = 30). Results: The MCP-1 levels and LVEF at baseline were comparable between the groups. However, after 12 months of treatment, the febuxostat group achieved significantly higher percent decreases in the UA and MCP-1 levels from baseline than those of the allopurinol group (p < 0.001). The LVEF in both groups had improved after 12 months; however, a greater percent increase in the LVEF from baseline was observed in the febuxostat group than that in the allopurinol group (p < 0.001). The percent increase in the LVEF from baseline was found to be significantly associated with the percent decrease in MCP-1 (r = −0.634, p < 0.001) in the febuxostat group. Conclusions: These data indicate that febuxostat is more effective than allopurinol in reducing the UA level and inflammation and may improve the cardiac function in CHF patients with hyperuricemia due, at least in part, to reductions in inflammation

A novel role for Helicobacter pylori cytotoxin-associated gene A in negative regulation of autophagy in human gastric cells

Abstract Background Autophagy plays an important role in carcinogenesis and tumor progression in many cancers, including gastric cancer. Cytotoxin-associated gene A (CagA) is a well-known virulent factor in Helicobacter pylori (H. pylori) infection that plays a critical role in gastric inflammation and gastric cancer development. However, its role in autophagy during these processes remains unclear. Therefore, we aimed to clarify the role of CagA in autophagy in CagA-related inflammation. Methods We evaluated the autophagic index of AGS cells infected with wild-type cagA-positive H. pylori (Hp-WT) and cagA-knockout H. pylori (Hp-ΔcagA) and rat gastric mucosal (RGM1) cells transfected with CagA genes. To identify the mechanisms underlying the down regulation of autophagy in AGS cells infected with H. pylori, we evaluated protein and mRNA expression levels of autophagy core proteins using western blotting and quantitative reverse transcription-polymerase chain reaction (RT-PCR). To determine whether autophagy induced the expression of the pro-inflammatory mediator, cyclooxygenase-2 (COX-2), we evaluated COX-2 expression in AGS cells treated with an autophagy inducer and inhibitor and infected with H. pylori. In addition, we evaluated whether COX-2 protein expression in AGS cells influenced beclin-1 (BECN1) expression with si-RNA transfection when infected with H. pylori. Results Autophagic flux assay using chloroquine showed that autophagy in AGS cells was significantly suppressed after H. pylori infection. The autophagic index of AGS cells infected with Hp-WT was decreased significantly when compared with that in AGS cells infected with Hp-ΔcagA. The autophagic index of RGM1 cells transfected with CagA was lower, suggesting that CagA inhibits autophagy. In addition, BECN1 expression levels in AGS cells infected with Hp-WT were reduced compared to those in AGS cells infected with Hp-ΔcagA. Furthermore, COX-2 expression in AGS cells infected with H. pylori was controlled in an autophagy-dependent manner. When AGS cells were transfected with small interfering RNA specific for BECN1 and infected with Hp-WT and Hp-ΔcagA, COX-2 was upregulated significantly in cells infected with Hp-ΔcagA. Conclusions In conclusion, the H. pylori CagA protein negatively regulated autophagy by downregulating BECN1. CagA-induced autophagy inhibition may be a causative factor in promoting pro-inflammatory mediator production in human gastric epithelial cells