miR-153 enhances the therapeutic effect of gemcitabine by targeting Snail in pancreatic cancer

Abstract

Pancreatic cancer (PC) is one of the most lethal cancers, with an overall 5 years survival rate of <5%. The clinical benefit of gemcitabine based chemotherapeutic strategy on PC was limited by its high drug resistance rate. Snail, one of the master regulators of epithelial–mesenchymal transition, has been implicated in the progression of various cancers. However, whether it is also linked to the development of chemosensitivity to gemcitabine in PC is unknown, and the regulatory pathways controlling Snail also need to be explored. Cell apoptosis analysis was performed using flow cytometry assay. Quantitative real-time PCR was used to investigate the level of microRNA and the mRNA expression of its target, Snail. Snail expression was measured by immunoblotting and immunohistochemistry. A xenografted tumor model was used to test the in vivo effects of miR-153 on chemosensitivity to gemcitabine. The results of this study demonstrated the decrease of miR-153 expression in PC tumor tissue, which is correlated with a poor prognosis. miR-153 mimic transfection enhanced gemcitabine sensitivity in gemcitabine-resistant PC cells, while downregulation of miR-153 decreased gemcitabine sensitivity. In addition, miR-153 was found to target the 3′-UTR of Snail mRNA. Furthermore, we found that the increase of apoptosis in gemcitabine-resistant PC cells resulted from miR-153 mimic transfection was reversed by overexpression of Snail. miR-153 reverses the resistance of PC cells to gemcitabine by directly targeting Snail, and it may be a potential novel therapeutic target for overcoming gemcitabine resistance in human PC.

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