Abstract
BackgroundNicotine, an active ingredient in tobacco, can promote epithelial-to-mesenchymal transition (EMT) processes that enhance the aggressiveness of a number of human cancers. In the present study, we investigated whether cigarette smoke/nicotine drives EMT in pancreatic ductal adenocarcinoma (PDAC).MethodsQuantitative real-time PCR, western blot, immunohistochemistry, and immunofluorescence assays were used to evaluate Yes-associated protein 1 (YAP1) expression associated with cigarette smoking in human PDAC tissue samples and with nicotine exposure in PDAC cell lines. Bioinformatics, loss- and gain- of- function experiments, luciferase reporter assays, chromatin immunoprecipitation (ChIP), and murine tumor xenograft models were performed to examine the function of YAP1 in PDAC and to identify potential mechanisms of action.ResultsExposure to smoking or nicotine promoted EMT and tumor growth in PDAC cells and in xenograft tumors. Functional studies revealed that YAP1 might drive nicotine-stimulated EMT and oncogenic activity in vitro and in vivo. In human PDAC tissues, upregulation of YAP1 was associated with “ever smoking” status and poor overall survival. In term of mechanism, hypoxia inducible factor (HIF)1A promoted YAP1 nuclear localization and YAP1 transactivation by directly binding to the hypoxia responsive elements of the YAP1 promoter upon nicotine treatment. Nicotine stimulated HIF1A and YAP1 expression by activating cholinergic receptor nicotinic alpha7 (CHRNA7). In addition, YAP1 increased and sustained the protein stability of HIF1A.ConclusionsThese data demonstrate that YAP1 enhances nicotine-stimulated EMT and tumor progression of PDAC through a HIF1A/YAP1 positive feedback loop. Developing inhibitors that specifically target YAP1 may provide a novel therapeutic approach to suppress PDAC growth, especially in PDAC patients who have a history of smoking.
Highlights
Nicotine, an active ingredient in tobacco, can promote epithelial-to-mesenchymal transition (EMT) processes that enhance the aggressiveness of a number of human cancers
Smoking/nic-induced EMT is accompanied by increased Yes-associated protein 1 (YAP1) expression in pancreatic ductal adenocarcinoma (PDAC) Our previous research indicated that nicotine induces an EMT process in PDAC cells [30]
Using IHC assays, we found that expression levels of E-cad were significantly lower, while expression levels of Vim were higher, in PDAC tumor tissue (TT) samples from patients who were “ever smokers” than from patients who were “never smokers” (Supplementary Fig. s1a and b)
Summary
An active ingredient in tobacco, can promote epithelial-to-mesenchymal transition (EMT) processes that enhance the aggressiveness of a number of human cancers. We investigated whether cigarette smoke/nicotine drives EMT in pancreatic ductal adenocarcinoma (PDAC). Pancreatic ductal adenocarcinoma (PDAC), the main type of pancreatic cancer, is a malignant solid tumor that has one of the highest mortality rates [1]. The epithelial-to-mesenchymal transition (EMT) plays a critical role in PDAC progression and metastasis [8, 9]. Nic can stimulate EMT and increase the aggressiveness of many types of cancer [11, 12]. It is unclear if Nic-induced EMT phenotypes occurs in the development of PDAC, and the mechanisms by which Nic may contribute to EMT and progression in PDAC are not completely known
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