Abstract
MicroRNAs (miRNAs) are involved in the epithelial-mesenchymal transition (EMT) process and are associated with metastasis in gastric cancer (GC). MiR-338-3p has been reported to be aberrantly expressed in GC. In the present study, we show that miR-338-3p inhibited the migration and invasion of GC cells in vitro. Knocking down miR-338-3p in GC cells led to mesenchymal-like changes. MiR-338-3p influenced the expression of the EMT-associated proteins by upregulating the epithelial marker E-cadherin and downregulating the mesenchymal markers, N-cadherin, fibronectin, and vimentin. In terms of mechanism, miR-338-3p directly targeted zinc finger E-box-binding protein 2 (ZEB2) and metastasis-associated in colon cancer-1 (MACC1). MiR-338-3p repressed the Met/Akt pathway after MACC1 inhibition. Reintroduction of ZEB2 and MACC1 reversed miR-338-3p-induced EMT suppression. Consistently, inverse correlations were also observed between the expression of miR-338-3p and ZEB2 or MACC1 in human GC tissue samples. In conclusion, miR-338-3p inhibited the EMT progression in GC cells by targeting ZEB2 and MACC1/Met/Akt signaling.
Highlights
The epithelial-mesenchymal transition (EMT) is considered as one of critical steps in gastric cancer (GC) cell invasion and metastasis, by which GC cells lose their epithelial phenotype and cell-cell adhesion and gain invasive mesenchymal properties [1,2,3]
In situ hybridization (ISH) showed that miR-338-3p was mainly localized in the cytoplasm of GC cells, with a certain amount detected in the cell nucleus (Figure 1B)
MiR-338-3p expression was lower in deeper invasion GC (T3-4 vs. T12), suggesting that its deficiency may contribute to GC cell invasiveness (Figure 1D, P = 0.031)
Summary
The epithelial-mesenchymal transition (EMT) is considered as one of critical steps in gastric cancer (GC) cell invasion and metastasis, by which GC cells lose their epithelial phenotype and cell-cell adhesion and gain invasive mesenchymal properties [1,2,3]. The molecular mechanisms of EMT are intricate. Certain transcription factors such as zinc finger E-box-binding protein (ZEB) are involved in EMT regulation in GC [35]. Recent studies have shown that microRNAs (miRNAs) via binding to the 3′ untranslated region (UTR) of some target genes cause the mRNA destabilization and protein downregulation, which may result in the repression of the EMT process [8,9,10]. GC miR-3383p expression is even lower in patients with deeper local invasion and advanced TNM stage [9]. These suggest that miR-338-3p is a biomarker of GC, but might be involved in EMT regulation that initiates GC cell invasion. The underlying mechanism of this process has not been well explored
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