Recent studies have demonstrated that acquisition of epithelial-to-mesenchymal transition (EMT) is associated with drug resistance in pancreatic cancer cells; however, the underlying mechanisms are not fully elucidated. Emerging evidence suggests that microRNAs play a crucial role in controlling EMT. The aims of this study were to explore the potential role of miR-223 in governing EMT in gemcitabine-resistant (GR) pancreatic cancer cells. To achieve this goal, real-time reverse transcription-PCR and western blot analysis were used to validate whether GR cells acquired EMT in AsPC-1 and PANC-1 cells. Invasion, migration, and detachment assays were performed to further identify the EMT characteristics in GR cells. The miR-223 inhibitor was used to determine its role in GR-induced EMT. We found that GR cells acquired EMT features, which obtained elongated fibroblastoid morphology, decreased expression of epithelial marker E-cadherin, and up-regulation of mesenchymal markers. Furthermore, we observed that GR cells are associated with high expression of miR-223. Notably, inhibition of miR-223 led to the reversal of EMT phenotype. More importantly, miR-223 governs GR-induced EMT in part due to down-regulation of its target Fbw7 and subsequent upregulation of Notch-1 in pancreatic cancer. Our study implied that down-regulation of miR-223 could be a novel therapy for pancreatic cancer.

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Although genistein has been shown to inhibit tumorigenesis in a variety of human cancers including pancreatic cancer (PC), the exact molecular mechanism of its anti-cancer effects has not yet been fully elucidated. Recently, microRNAs (miRNAs) have been reported to regulate multiple aspects of tumor development and progression, indicating that targeting miRNAs could be a novel strategy to treat human cancers. In the current study, we investigated whether a natural compound genistein could down-regulate onco-miR-223, resulting in the inhibition of cell growth and invasion, and induction of apoptosis in PC cells. We found that genistein treatment significantly inhibited miR-223 expression and up-regulated Fbw7, one of the targets of miR-223. Moreover, down-regulation of miR-223 inhibited cell growth and induced apoptosis in PC cells. These findings suggest that genistein exerts its anti-tumor activity partly through downregulation of miR-223 in PC cells.

Our findings demonstrated that genistein plays a tumor suppressor role in part through inhibition of miR-27a in pancreatic cancer cells.

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