Hypoxia-inducible factor-2α promotes EMT in esophageal squamous cell carcinoma through the Notch pathway.

BACKGROUND: Esophageal cancer is one of the most lethal tumors worldwide. The most common histological type in China is esophageal squamous cell carcinoma (ESCC), accounting for 90% of cases. Esophageal cancer occurs at a high incidence in certain areas, among which China has the highest incidence. Although various therapeutic strategies have been used in clinical treatment, the 5-year survival rate is still not satisfactory, as it is only 15-20%. The reason for the poor prognosis of ESCC is that the distant metastasis easily occurs in these tumors. However, the mechanism of metastasis has not been studied clearly. OBJECTIVES: To investigate the function of hypoxia-inducible factor-2α (hif-2α) in ESCC. MATERIAL AND METHODS: Immunohistochemistry and immunofluorescence were used to detect the expression of hif-2α in tissues and cells. Clinicopathological data from 100 ESCC patients were used to investigate the relationship between hif-2α and prognosis. Cell experiments (Cell Counting Kit-8 (CCK-8) assay and transwell migration assays) were utilized to verify the roles of hif-2α on the ESCC cells. Western blotting was used to explore the mechanism of hif-2α in ESCC. Mouse model was used to clarify the effect of hif-2α on ESCC cells in vivo. RESULTS: The hif-2α was overexpressed both in ESCC tissues and cells, and was related with poor prognosis in ESCC patients. The CCK-8 assay evidenced that silencing hif-2α suppressed the proliferation of ESCC cells, while transwell assay - that overexpression of hif-2α promoted the migration of ESCC cells. Western blot assay indicated that hif-2α regulated epithelial-mesenchymal transition (EMT) through Notch pathway in ESCC cells. Mouse model showed that silencing hif-2α significantly suppressed the proliferation of ESCC cells in vivo. CONCLUSIONS: The hif-2α promotes EMT in ESCC through the Notch pathway.

Identification of an Innate Immune-Related Prognostic Signature in Early-Stage Lung Squamous Cell Carcinoma.

BACKGROUND: Early-stage lung squamous cell carcinoma (LUSC) progression is accompanied by changes in immune microenvironments and the expression of immune-related genes (IRGs). Identifying innate IRGs associated with prognosis may improve treatment and reveal new immunotherapeutic targets. METHODS: Gene expression profiles and clinical data of early-stage LUSC patients were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases and IRGs from the InnateDB database. Univariate and multivariate Cox regression and LASSO regression analyses were performed to identify an innate IRG signature model prognostic in patients with early-stage LUSC. The predictive ability of this model was assessed by time-dependent receiver operator characteristic curve analysis, with the independence of the model-determined risk score assessed by univariate and multivariate Cox regression analyses. Overall survival (OS) in early-stage LUSC patients was assessed using a nomogram and decision curve analysis (DCA). Functional and biological pathways were determined by gene set enrichment analysis, and differences in biological functions and immune microenvironments between the high- and low-risk groups were assessed by ESTIMATE and the CIBERSORT algorithm. RESULTS: A signature involving six IRGs (SREBF2, GP2, BMX, NR1H4, DDX41, and GOPC) was prognostic of OS. Samples were divided into high- and low-risk groups based on median risk scores. OS was significantly shorter in the high-risk than in the low-risk group in the training (P < 0.001), GEO validation (P = 0.00021) and TCGA validation (P = 0.034) cohorts. Multivariate Cox regression analysis showed that risk score was an independent risk factor for OS, with the combination of risk score and T stage being optimally predictive of clinical benefit. GSEA, ESTIMATE, and the CIBERSORT algorithm showed that immune cell infiltration was higher and immune-related pathways were more strongly expressed in the low-risk group. CONCLUSION: A signature that includes these six innate IRGs may predict prognosis in patients with early-stage LUSC.

EPB41L5 promotes EMT through the ERK/p38 MAPK signaling pathway in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors worldwide and is characterized by activation of epithelial-mesenchymal transition (EMT). EPB41L5 is regarded as a key factor in the progression of EMT and metastasis in various kinds of cancers, although the role and mechanism of EPB41L5 in ESCC have not yet been elucidated. In addition, tumor cells can acquire enhanced aggressiveness and a mesenchymal phenotype through phosphorylation of MAPK signaling pathway components. Here, we intend to explore whether EPB41L5 can regulate the EMT process in ESCC and reveal whether the MAPK signaling pathway is involved. METHODS: We compared the expression level of EPB41L5 with the prognostic characteristics of 100 ESCC patients to hypothesize the role of EPB41L5 in the progression of ESCC. Furthermore, in vivo and in vitro experiments were conducted to verify the conclusions from the analysis of clinical specimens and investigate the underlying mechanism by which EPB41L5 contributes to ESCC. RESULTS: We discovered that EPB41L5 was overexpressed in ESCC and that higher EPB41L5 expression was related to higher TNM stage, a higher incidence of lymphatic metastasis and worse prognosis. Moreover, using ESCC cells and nude mouse models, we found that EPB41L5 promoted EMT, proliferation, migration and invasion in ESCC. Mechanistically, activation of phosphorylation in the ERK/p38 MAPK signaling pathway was involved in the EPB41L5-mediated regulation of EMT. CONCLUSION: In conclusion, our findings suggest that EPB41L5 plays a critical role in the regulation of EMT and the progression of ESCC.