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

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.

Yap1-2 Isoform Is the Primary Mediator in TGF-β1 Induced EMT in Pancreatic Cancer

“…Interestingly, YAP1 has been shown to be involved in both oncogenic KRAS-dependent and KRAS-independent cancer-promoting activities ( 4 , 5 ). In recent years, YAP1 has been reported to participate in Epithelial-to-mesenchymal transition (EMT) process of tumor cells ( 6 , 7 ).…”

Sevoflurane inhibits neuroblastoma cell proliferation and invasion and induces apoptosis by miR‐144‐3p/YAP1 axis

“…YAP is the coding product of the YAP1 gene, and Yang et al 40 found that YAP is a new regulator of NB cell proliferation, tumourigenesis and invasion, as well as an underlying target for treating cisplatin‐resistant NB. Previous studies have proved that YAP1 is widely involved in NB as an oncoprotein 16,17 . Meanwhile, tetrandrine (Tet) induces NB cell apoptosis by attenuating the Hippo/YAP1 pathway, 41 confirming that YAP1 is an oncogene in NB cells.…”

“…In addition, inhibiting YAP1 hampers epithelial–mesenchymal transition (EMT) of pancreatic ductal adenocarcinoma 15 . Similarly, YAP1 is overexpressed in NB, and inhibiting YAP1 significantly represses NB cell proliferation, migration and invasion 16,17 . These reports indicate that YAP1 is implicated in NB, but whether SEV mediates NB progression through the miR‐144‐3p/YAP1 axis needs more exploration.…”

Identified GNGT1 and NMU as Combined Diagnosis Biomarker of Non-Small-Cell Lung Cancer Utilizing Bioinformatics and Logistic Regression

“…Cigarette smoking is a well-known risk factor for the occurrence and progression of malignant diseases [ 82 – 85 ]. Nicotine, the major constituent in cigarette smoke, plays key roles in cancer progression [ 86 – 89 ]. Nicotine likely promotes lung cancer cell proliferation by upregulating HIF-1 α and SOCC components [ 90 – 93 ].…”