miR-145 inhibits colorectal cancer progression and metastasis by targeting SNAI1 and the cAMP/PKA pathway

BACKGROUND: Transcriptional repressor 1 of the Snail family (SNAI1) and miR-145 play crucial roles in the development of colon cancer. Tumor invasiveness and epithelial-mesenchymal transition (EMT) are associated with SNAI1, whereas miR-145 is considered a tumor suppressor. Although cAMP/PKA signaling is critical for regulating cell survival and invasiveness, the precise mechanisms through which SNAI1 and miR-145 influence tumor cell behavior via this pathway remain unclear. OBJECTIVES: To examine the mechanisms by which SNAI1 and miR-145 regulate colon cancer cell invasion and survival through the cAMP/PKA signaling pathway and to assess their functional relationship. MATERIAL AND METHODS: SNAI1 and miR-145 were overexpressed in the colon cancer cell lines DLD1 and HCT116, respectively, and cAMP and PKA activity was assessed using quantitative real-time PCR (qPCR) and western blot analysis. In addition, a luciferase reporter assay and application of the PKA inhibitor H89 were used to further investigate the roles of SNAI1 and miR-145 in regulating cell invasion and survival. RESULTS: Overexpression of SNAI1 significantly increased cAMP and PKA activity and promoted cell survival and invasion. However, overexpression of miR-145 decreased cell invasion and survival by blocking the cAMP/PKA signaling pathway. When both were overexpressed, miR-145 further decreased cAMP/PKA activity and inhibited the tumor-promoting effects of SNAI1. Use of the PKA inhibitor H89 also reduced the tumor-promoting effect of SNAI1. CONCLUSIONS: By activating the cAMP/PKA signaling pathway, SNAI1 promotes colon cancer cell survival and invasion, whereas miR-145 suppresses tumor progression by inhibiting this pathway. These findings suggest that SNAI1 and miR-145 may represent viable therapeutic targets for colon cancer treatment and that targeting the cAMP/PKA pathway may provide a novel therapeutic strategy.