The median survival time of patients with advanced gastric cancer (GC) who received radiotherapy and chemotherapy was <1 year. Epithelial–mesenchymal transformation (EMT) gives GC cells the ability to invade, which is an essential biological mechanism in the progression of GC. The long non-coding RNA (lncRNA)-based competitive endogenous RNA (ceRNA) system has been shown to play a key role in the GC-related EMT process. Although the AKT pathway is essential for EMT in GC, the relationship between AKT3 subtypes and EMT in GC is unclear. Here, we evaluated the underlying mechanism of ceRNA involving NR2F1-AS1/miR-190a/PHLDB2 in inducing EMT by promoting the expression and phosphorylation of AKT3. The results of bioinformatics analysis showed that the expression of NR2F1-AS1/miR-190a/PHLDB2 in GC was positively associated with the pathological features, staging, poor prognosis, and EMT process. We performed cell transfection, qRT-PCR, western blot, cell viability assay, TUNEL assay, Transwell assay, cell morphology observation, and double luciferase assay to confirm the regulation of NR2F1-AS1/miR-190a/PHLDB2 and its effect on EMT transformation. Finally, GSEA and GO/KEGG enrichment analysis identified that PI3K/AKT pathway was positively correlated to NR2F1-AS1/miR-190a/PHLDB2 expression. AKT3 knockout cells were co-transfected with PHLDB2-OE, and the findings revealed that AKT3 expression and phosphorylation were essential for the PHLDB2-mediated EMT process. Thus, our results showed that NR2F1-AS1/miR-190a/PHLDB2 promoted the phosphorylation of AKT3 to induce EMT in GC cells. This study provides a comprehensive understanding of the underlying mechanism involved in the EMT process as well as the identification of new EMT markers.
BackgroundTransforming growth factor-beta (TGF-β) signaling is essential in initialization and progression of hepatocellular carcinoma (HCC). Therefore, a treatment targeting TGF-β pathway may be a promising option for HCC control.MethodsFirst, publicly available RNA-seq datasets and clinical characteristics of 374 HCC patients in The Cancer Genome Atlas (TCGA) database were downloaded. Then, Cox regression analysis and LASSO analysis were used to construct a prognostic model for TGF-β family genes. The area under the curve (AUC) of the risk signature was calculated to evaluate the predictive power of the model. Cox regression analysis was applied to predict whether TGF-β1 can be an independent prognosis factor for HCC. Next, hazard ratio and survival analyses were performed to investigate the correlation between TGF-β1 expression and survival time. Furthermore, differential expression level of TGF-β1 in HCC tissues and cells was determined. In addition, Gene Set Enrichment Analysis (GSEA) identified the top significantly activated and inhibited signal pathways related to high expression of TGF-β1. Finally, the CIBERSORT tool was adopted to correlate the tumor-infiltrating immune cells (TICs) with TGF-β1 expression in HCC cohorts.ResultsCox regression analysis and LASSO analysis revealed that seven TGF-β family members (including TGF-β1) could be used as prognostic factors for HCC. Interestingly, TGF-β1 was demonstrated to be an independent prognostic factor of HCC. RT-qPCR and immunofluorescence staining confirmed the high expression of TGF-β1 in HCC cell lines and tissues, which is significantly related to pathological classifications, poor prognosis, and short survival time. Finally, GSEA and CIBERSORT analyses suggested that TGF-β1 may interact with various immune cells and influence the prognosis of HCC patients through Tregs and γδ T cells.ConclusionWe established a novel prognostic prediction method to predict the risk scores of TGF-β genes in HCC prognosis. TGF-β1 is highly expressed in HCC cell lines and tissues, correlates to poor prognosis, and thus can be used as a potential biomarker to predict HCC prognosis. We showed that TGF-β1 may play its roles in HCC prognosis by modulating the immune microenvironment of tumor cells. Our data may shed more light on better understanding the role of TGF-β1 in HCC prognosis.
Nonalcoholic fatty liver disease (NAFLD), a chronic condition associated with metabolic dysfunction and obesity, has reached epidemic proportions worldwide. Although early NAFLD can be treated with lifestyle changes, the treatment of advanced liver pathology, such as nonalcoholic steatohepatitis (NASH), remains a challenge. There are currently no FDA-approved drugs for NAFLD. Fibroblast growth factors (FGFs) play essential roles in lipid and carbohydrate metabolism and have recently emerged as promising therapeutic agents for metabolic diseases. Among them, endocrine members (FGF19 and FGF21) and classical members (FGF1 and FGF4) are key regulators of energy metabolism. FGF-based therapies have shown therapeutic benefits in patients with NAFLD, and substantial progress has recently been made in clinical trials. These FGF analogs are effective in alleviating steatosis, liver inflammation, and fibrosis. In this review, we describe the biology of four metabolism-related FGFs (FGF19, FGF21, FGF1, and FGF4) and their basic action mechanisms, and then summarize recent advances in the biopharmaceutical development of FGF-based therapies for patients with NAFLD.
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