CREB1 Suppresses Transcription of microRNA-186 to Promote Growth, Invasion and Epithelial-Mesenchymal Transition of Gastric Cancer Cells Through the KRT8/HIF-1α Axis.

ABSTRACT

BACKGROUND: The cAMP response element-binding protein 1 (CREB1) was initiated as a potential target for cancer treatment. This research was conducted to probe the effect of CREB1 in the progression of gastric cancer (GC) and the molecules involved. MATERIALS AND METHODS: CREB1 expression in GC tissues and cell lines (AGS and MKN-45) as well as that in normal tissues and in gastric mucosa cell line (GES-1) was detected. The correlation between CREB1 expression and prognosis of GC patients was determined. Artificial silencing of CREB1 was introduced to evaluate its effect on biological behaviors of GC cells. The target microRNA (miRNA) of CREB1 and the target mRNA of miR-186 were predicted and validated. Altered expression of miR-186, KRT8 and HIF-1α was introduced to confirm their functions in GC progression. RESULTS: CREB1 was abundantly expressed in GC tissues and cells and linked to dismal prognosis in patients. Silencing of CREB1 or upregulation of miR-186 suppressed the malignant behaviors such as growth, epithelial-mesenchymal transition (EMT) and invasion of GC cells, while artificial overexpression of KRT8 led to reversed trends. KRT8 was a target mRNA of miR-186, and CREB1 transcriptionally suppressed miR-186 expression to further up-regulate KRT8. KRT8 was also found to increase HIF-1α expression. Upregulation of HIF-1α was found to block the suppressing role of CREB1 silencing in GC cell malignancy. CONCLUSION: This study evidenced that silencing of CREB1 inhibits growth, invasion, EMT and resistance to apoptosis of GC cells involving the upregulation of miR-186 and the following downregulation of KRT8 and HIF-1α.