The farnesoid X receptor (FXR), a ligand-activated transcription factor belonging to the adopted orphan receptor, plays an important role in maintaining health of the liver and intestine. In this study, we identified individual bacterial strains that directly modulated the activation of intestinal FXR. The FXR stimulatory potential of 38 bacterial strains was determined using a stable FXR reporter system derived from intestinal epithelial cells (IEC). The induction of FXR target genes by screened FXR stimulatory bacteria was determined by real-time PCR. In addition, a high fat diet (HFD)-induced obese mouse model was used to evaluate in vivo FXR stimulatory potential of bacterial metabolites screened in this study. A luciferase assay with the FXR reporter cell line demonstrated that the FXR-stimulatory activity of most bacterial cell samples was less than 2-fold. The culture supernatants of Bacteroides dorei and Eubacterium limosum induced FXR activity and selectively regulated FXR target expression in the FXR reporter system. Treatment with B. dorei-derived metabolites strongly induced ileal bile acid binding protein (IBABP) (8.4-fold) and organic solute transporter (OST) α (3.1-fold) compared with E. limosum-derived metabolites. Furthermore, administration of B. dorei derived metabolites showed significant reduction in body weight gain, and both two bacterial metabolites reduced liver weight in obese mice compared to PBS-treated controls. Administration of each bacterial metabolites improved in serum levels of obesity-related metabolic biochemical markers such as ALT, AST, total cholesterol, and triglyceride. Furthermore, two bacterial metabolites enhanced the Fxr gene expression in the intestine and liver, and ileal Shp gene expression tended to be increased by treatment with the metabolites derived from B. dorei. B. dorei and E. limosum secreted the bioactive substances that directly stimulate FXR in the intestinal epithelial cells. Administration of these bacterial FXR-stimulatory metabolites improves the obesity phenotype including body weight gain, liver damage, lipid metabolism in DIO mice.

Gastric cancer (GC) is the fourth most common malignant neoplasm and the second leading cause of cancer death. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression facilitates early GC diagnosis and the development of targeted therapies for advanced GC patients. Emerging evidence has revealed a close correlation between forkhead box (FOX) proteins and cancer development. However, the prognostic significance of forkhead box S1 (FOXS1) in patients with GC and the function of FOXS1 in GC progression remain undefined. In this study, we found that upregulation of FOXS1 was frequently detected in GC tissues and strongly correlated with an aggressive phenotype and poor prognosis. Functional assays confirmed that FOXS1 knockdown suppressed cell proliferation and colony numbers, with induction of cell arrest in the G0/G1 phase of the cell cycle, whereas forced expression of FOXS1 had the opposite effect. Additionally, forced expression of FOXS1 accelerated tumor growth in vivo and increased cell migration and invasion through promoting epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Mechanistically, the core promoter region of FOXS1 was identified at nucleotides −660~ +1, and NFKB1 indirectly bind the motif on FOXS1 promoters and inhibit FOXS1 expression. Gene set enrichment analysis revealed that the FOXS1 gene was most abundantly enriched in the hedgehog signaling pathway and that GLI1 expression was significantly correlated with FOXS1 expression in GC. GLI1 directly bound to the promoter motif of FOXS1 and significantly decreased FOXS1 expression. Finally, we found that miR-125a-5p repressed FOXS1 expression at the translational level by binding to the 3′ untranslated region (UTR) of FOXS1. Together, these results suggest that FOXS1 can promote GC development and could be exploited as a diagnostic and prognostic biomarker for GC.

Purpose: Gastric cancer (GC) is the fifth most common tumor in the world, and most patients with GC have a poor prognosis. This study aimed to explore the biological influence and mechanism of LINC01272 in GC. Materials and Methods: Using bioinformatic analyses, we investigated the expression of LINC01272 in TCGA database and predicted the biological functions and mechanism of LINC01272 in GC. Then, we detected the expression of LINC01272 in GC cell lines, GC tissues, and corresponding normal tissues using real-time polymerase chain reaction (RT-PCR). Finally, we explored the migration and invasion ability of LINC01272 by wound-healing and Transwell assays and examined the expression of epithelial-mesenchymal transition (EMT)-related proteins through Western blotting. Results: We found that LINC01272 was upregulated in GC and was associated with GC staging and lymph node metastasis. The results of wound-healing and Transwell assays revealed that the LINC01272 was closely related to GC cell migration and invasion. LINC01272 knockdown inhibited the migration and invasion ability of GC cells by reducing the expression of EMT-related proteins. Overexpression of LINC01272 had the opposite effect. Conclusion: Together, our results showed that LINC01272 promoted GC metastasis ability by regulating the expression of EMT-related proteins and could serve as a potential diagnostic biomarker for GC.