Gastric cancer (GC) is one of the most common and fatal types of cancers worldwide and the specific mechanism has not been completely elucidated. microRNA (miR)-3664-5P has rarely been studied and the aim of the present study was to assess an association between miR-3664-5P and GC. Differences in miR-3664-5P expression in 100 GC (0.1846±0.08276) and paired normal tissues (0.4382±0.1595) were detected using reverse transcription-quantitative polymerase chain reaction assays (P<0.001). 5-Ethynyl-2-deoxyuridine, Cell Counting Kit-8, transwell and flow cytometry assays were performed in vitro and the results were further verified using a mouse xenotransplantation and a lung metastasis model in vivo. miR-3664-5P was significantly downregulated in GC tissues when compared with normal tissues and positively associated with the prognosis of patients with GC (P<0.001). Overexpression of miR-3664-5P suppressed and miR-3664-5P knockdown promoted the proliferation and metastasis of GC cells in vitro and in vivo. Following the application of bioinformatic algorithms and luciferase reporter assays, metadherin (MTDH) was confirmed as the target gene of miR-3664-5P. miR-3664-5P reduced MTDH expression and downregulated the nuclear factor (NF)-κB signaling pathway. Rescue experiments demonstrated that suppression of MTDH restored the effect of miR-3664-5P inhibitors on GC cell lines. The results suggested that miR-3664-5P suppressed the proliferation and metastasis of GC cells by attenuating the NF-κB signaling pathway via MTDH targeting. Consequently, miR-3664-5P may have potential to be an independent prognostic factor and biomarker in GC.
Background: Characterized by the presence of inflammation, fibrosis, and bile duct proliferation, cholestatic liver disease (CLD) affects people of all age groups. Takeda G-protein-coupled receptor (TGR5) has been implicated in the suppression of inflammation via toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB). Kupffer cells and their M1 polarization play important roles in inflammation and cholestatic liver injury via production of pro-inflammatory cytokines. Nevertheless, the function of TGR5 signaling in CLD is largely unknown.Methods: We conducted liver tissue experiments, animal experiments, serum marker testing, liver histology analysis, Kupffer cell experiments, RNA extraction and Real-time PCR, western blotting, evaluation of ROS production by flow cytometry and statistical differences were analyzed by student t-test using GraphPad Prism.Results: We found that serum bile acid (BA) and TGR5 levels were elevated in patients with cholestasis cirrhosis. Knockout of TGR5 in animals significantly increased bile duct ligation (BDL)-caused liver injury through increasing oxidative stress, promoting M1-predominant polarization of Kupffer cells, and elevating the serum levels of inflammatory cytokines. In contrast, TGR5 activation inhibited ROS production, secretion of pro-inflammatory cytokines, and M1-predominant polarization of Kupffer cells. Moreover, results showed that TGR5 exerted its effects via suppressing NF-κB signaling and activating nuclear factor 2 (Nrf2)/HO-1 signaling. Finally, the effect of TGR5 on cholestatic liver damage was also confirmed in vivo.Conclusions: TGR5 activation protected against BDL-induced CLD by both suppressing inflammation via inhibiting the NF-κB pathway and reducing ROS production via activation of Nrf2/HO-1 signaling.These findings show the importance of TGR5 in CLD and provide new insight into therapeutic strategies for CLD.
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