Forkhead box K1 (FOXK1) is a transcription factor belonging to the Forkhead box (FOX) family and is closely related to the development of various cancers, but the functional mechanism through which FOXK1 regulates autophagy and epithelial-mesenchymal transition (EMT) in the acidic microenvironment of gastric cancer (GC) remains unclear. Our results indicated that the inhibition of FOXK1 induced autophagy and thus exerted antimetastatic effects in an acidic microenvironment. The dual inhibition of mammalian target of rapamycin (mTOR) and FOXK1 enhanced autophagy and reversed EMT of acidic GC cells. In addition, FOXK1 activated transcription in conjunction with the MAZ promoter. Together, our results suggest that FOXK1 can be used as an independent prognostic indicator for GC patients. We also revealed a new strategy involving the cotargeting of FOXK1 and autophagy to reverse the effects of EMT. MAZ is involved in the development and progression of GC as a downstream target of FOXK1. Here, the cellular responses to the inhibition of FOXK1 in GC were studied in vivo and in vitro through wound healing assays, transwell assays, Western blotting, laser confocal microscopy and transmission electron microscopy. The molecular mechanisms of FOXK1 and Myc-associated zinc finger protein (MAZ) were studied via chromatin immunoprecipitation sequencing (ChIP-seq), bioinformatics, Western blotting, and quantitative real-time PCR (q-PCR).

Background: Gastric cancer (GC) is a common malignancy of the digestive system. Antioxidant activity is regarded as a possible mechanism in ectopic cancer. Hence, oxidative stress regulation is being evaluated for cancer treatment. Previous research has demonstrated that Nestin is associated with antioxidative resistance via its modulation of the Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Methods: We determined the role of Nestin-mediated redox homeostasis and tumor phenotypes in GC cells. Results: We found that the Nestin expression level was high in GC tissues and cell lines. Nestin knockdown in the GC cell lines SGC-7901 and MKN-45 reduced viability, induced apoptosis, decreased antioxidant enzyme generation, and repressed GC metastasis. Nestin binds to Keap1, resulting in Nrf2 degradation and influencing downstream gene expression. Nestin knockdown resulted in the downregulation of Nrf2 expression in GC cells. The restoration of Nrf2 expression or treatment with the Nrf2 activator sulforaphane counteracted the inhibitory effect of Nestin knockdown on the proliferation, migration, invasion, and antioxidant enzyme production in GC cells. Moreover, xenograft GC tumors exhibited a slower growth rate than those of the control group in vivo. Conclusions: Taken together, these findings suggest that the Nestin–Keap1–Nrf2 axis confers oxidative stress resistance and plays an important role in the proliferation, migration, and invasion of GC cells.

Objective: The aim of this study was to use bioinformatic analyses to identify key genes and pathways driving gastric cancer (GC). Materials and Methods: The gene expression profiles, from human gastric tissue samples were downloaded from the Gene Expression Omnibus (GSE)29272 dataset. These data revealed 284 differentially expressed genes (DEGs) that included a group upregulated in cancer tissues ( n = 142) and another group that were downregulated in cancer tissues. ( n = 142). These DEGs were identified using the GEO2R. We used multiple online analysis tools, including, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction networks, gene expression profiling interactive analysis (GEPIA), and the cBio Cancer Genomics Portal (cBioportal) database. Next, we identified the most significant DEGs using the Kaplan-Meier plotter (KM-plotter) database. Multiple bioinformatic platforms were used to identify candidate prognostic marker genes. We then analyzed freshly frozen GC tissues for the expression of these marker genes to validate the informatic findings. Results: We identified three DEGs related to overall survival from our analyses of the GEO data. Next, we analyzed these three DEGs in GEPIA and the cBioportal database and found that the biglycan ( BGN ) gene was related to invasion and metastases of GCs. This finding of differential gene expression was confirmed in a separate laboratory analysis of normal and GC tissues. In this analysis we found that high levels of BGN expression were correlated with GC clinicopathological characteristics, including microvascular tumor thrombus ( p = 0.018), lymph node metastases ( p = 0.013), and vessel invasion ( p = 0.004). Conclusions: BGN expression levels appear to be an independent prognostic factor for predicting the survival times of GC patients.

Background: Forkhead box K1 (FOXK1) is a transcription factor that contributes to cancer development, but it is unclear how FOXK1 regulates the proliferation and migration of gastric cancer (GC) cells. The purpose of this study was to investigate the clinical significance, biological function, and molecular mechanisms of FOXK1 in GC. Methods: We conducted bioinformatics assays and western blotting to assess FOXK1 expression. Then, we performed immunohistochemistry (IHC) with tissue microarrays (TMAs) to assess FOXK1 expression in order to identify an association between FOXK1 expression levels and clinical parameters. We used 5-ethynyl-2’-deoxyuridine (EdU), wound healing and Transwell assays to determine whether FOXK1 promotes malignant behaviors in GC. Furthermore, immunofluorescence staining, transmission electron microscopy and western blotting were used to verify an association between FOXK1 and autophagy. Results: We observed high levels of FOXK1 expression in GC tissues, which were associated with the degree of malignancy in GC. FOXK1 promotes the malignant behavior of GC by regulating autophagy via activation of the class I phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and inhibition of the expression of class III PI3K. Conclusions: These findings provide a new target for the comprehensive treatment of GC by highlighting the relationship between FOXK1 and malignant behaviors in GC.