MicroRNA-34a Contributes To EMT In Chronic Pancreatitis And Pancreatic Cancer By Targeting SIRT1and NOTCH1

Purpose:Evidence indicates chronic pancreatitis (CP) as a risk for pancreatic cancer (PC). Epithelial-mesenchymal transition (EMT) is supposed to contribute to inflammation and tumorigenesis, implying EMT may involve in the carcinogenesis of PC from CP. Thus, this study aims to investigate EMT in CP and PC as well as its potential regulating pathway.Experimental Design:EMT profiles, miR-34a and its targets SIRT1/NOTCH1were detected in both CP and PC samples. TGF-β induced EMT in PC cells was applied to explore the potential functional roles of miR-34a-SIRTl/NOTCH1pathway in EMT. We further observed the correlation between miR-34a expression and clinicopathological characteristics of PC patients.Results:Compared to normal pancreatic tissues, CP and PC tissues showed remarkable expression of EMT makers, down-regulated miR-34a, as well as overexpressed SIRT1and NOTCH1. Further, co-localization fluorescence experiments demonstrated active EMT process in CP and PC tissues, In addition, TGF-β induced EMT in PC cells showed down-regulated miR-34a as well as up-regulated SIRT1and NOTCH1. Consistently, inhibition of miR-34a also induced EMT in PC cells. On the contrary, restoration of miR-34a and inhibition of SIRT1/NOTCH1both remarkably induced MET in TGF-P treated PC cells. Finally, the clinical data revealed miR-34a expression was negatively correlated to advanced tumor stage, lymphatic invasion, vascular infiltration and distant metastasis.Conclusion:In response to the inflammatory microenvironment, TGF-β may down-regulate miR-34a expression and then induce EMT in CP and PC by absenting the inhibition of SIRT1and NOTCH1, which might involve in carcinogenesis and progression of PC.