miR-146a-5p mediates epithelial-mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2.

This corrects the article DOI: 10.1038/bjc.2016.367.

miR-146a-5p mediates epithelial-mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2.

BACKGROUND: Our previous study found that dysregulated microRNA-146a-5p (miR-146a-5p) is involved in oesophageal squamous cell cancer (ESCC) proliferation. This article aimed to evaluate its detailed mechanisms in ESCC epithelial-mesenchymal transition (EMT) progression. METHODS: Invasion assay, qRT-PCR and western blotting were used to validate the roles of miR-146a-5p and Notch2 in EMT progression. miRNA target gene prediction databases and dual-luciferase reporter assay were used to validate the target gene. RESULTS: miR-146a-5p inhibitor led to increase of invaded ESCC cells, while miR-146a-5p mimics inhibited invasion ability of ESCC cells. Protein level of E-cadherin decreased, whereas those of Snail and Vimentin increased in the anti-miR-146a-5p group, which demonstrated that miR-146a-5p inhibits EMT progression of ESCC cells. miRNA target gene prediction databases indicated the potential of Notch2 as a direct target gene of miR-146a-5p and dual-luciferase reporter assay validated it. Importantly, shRNA-Notch2 restrained EMT and partially abrogated the inhibiting effects of miR-146a-5p on EMT progression of ESCC cells. CONCLUSIONS: miR-146a-5p functions as a tumour-suppressive miRNA targeting Notch2 and inhibits the EMT progression of ESCC.

Clinical potential of miR-3651 as a novel prognostic biomarker for esophageal squamous cell cancer.

Accumulating evidence indicates that dysregulated microRNA-3651(miR-3651) is involved in tumorigenesis and cancer progression. In this study, we investigated the expression of miR-3651 in esophageal squamous cell cancer(ESCC) and its relationship with tumor progression and clinical prognosis. The expression level of miR-3651 was examined by quantitative Real-time PCR (qRT-PCR) in fresh ESCC tissues and FFPE tissues. The correlation between miR-3651 expression and clinical features and prognosis were statistically analyzed. The results showed that the miR-3651 expression was significantly down-regulated in tumor tissues compared with the paracancerous tissues. Moreover, miR-3651 expression was negatively correlated with T stage of ESCC (P = 0.022) and tumor length (P = 0.015). Kaplan-Meier analysis demonstrated that low miR-3651 expression level was associated with poorer overall survival (OS) (P = 0.004) and disease-free survival (DFS) (P = 0.001). Multivariate analysis identified miR-3651 expression as independent prognostic factor for OS and DFS (P = 0.001 and P = 0.001, resp.). Further stratified analysis revealed the significant association between low miR-3651 expression and worse survival in early patients, but not in the advanced patients. Taken together, miR-3651 was down-regulated in cancerous tissues of ESCC. It may play an important role in cancer progression and could be used as an independent prognostic biomarker for ESCC patients.

Irradiated fibroblasts promote epithelial-mesenchymal transition and HDGF expression of esophageal squamous cell carcinoma.

Recent evidence suggested that nonirradiated cancer-associated fibroblasts (CAFs) promoted aggressive phenotypes of cancer cells through epithelial-mesenchymal transition (EMT). Hepatoma-derived growth factor (HDGF) is a radiosensitive gene of esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the effect of irradiated fibroblasts on EMT and HDGF expression of ESCC. Our study demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of ESCC cells and the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. Scattering of ESCC cells was also accelerated by the supernatant from irradiated fibroblasts. Exposure of ESCC cells to supernatant from irradiated fibroblasts resulted in decreased E-cadherin, increased vimentin in vitro and ß-catenin was demonstrated to localize to the nucleus in tumor cells with irradiated fibroblasts in vivo models. The expression of HDGF and ß-catenin were increased in both fibroblasts and ESCC cells of irradiated group in vitro and in vivo models. Interestingly, the tumor cells adjoining the stromal fibroblasts displayed strong nuclear HDGF immunoreactivity, which suggested the occurrence of a paracrine effect of fibroblasts on HDGF expression. These data suggested that irradiated fibroblasts promoted invasion, growth, EMT and HDGF expression of ESCC.