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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2020

Open Access 01-12-2020 | Research

A nicotine-induced positive feedback loop between HIF1A and YAP1 contributes to epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma

Authors: Qiwen Ben, Wei An, Yunwei Sun, Aihua Qian, Jun Liu, Duowu Zou, Yaozong Yuan

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

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Abstract

Background

Nicotine, 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).

Methods

Quantitative 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.

Results

Exposure 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.

Conclusions

These 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.
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Metadata
Title
A nicotine-induced positive feedback loop between HIF1A and YAP1 contributes to epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma
Authors
Qiwen Ben
Wei An
Yunwei Sun
Aihua Qian
Jun Liu
Duowu Zou
Yaozong Yuan
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-01689-6

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