Down-Regulation of the Canonical Wnt β-Catenin Pathway in the Airway Epithelium of Healthy Smokers and Smokers with COPD

Wang, Rui; Ahmed, Joumana; Wang, Guoqing; Hassan, Ibrahim A.; Strulovici-Barel, Yael; Hackett, Neil R.; Crystal, Ronald G.

doi:10.1371/journal.pone.0014793

Cited by 91 publications

(94 citation statements)

References 73 publications

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“…Although Heijink et al found that CSE decreased WNT4 and other WNT components in 16HBECs, 30 they did not study the potential role of the decreased WNT pathway in CS-related airway inflammation. Interestingly, it has been found that the mRNA levels of β-catenin were downregulated in the primary airway epithelium of smokers and smokers with COPD 13 and the number of β-catenin-positive staining alveolar epithelial cells were decreased in COPD patients compared with controls. 12 These studies suggested a crucial role of the WNT/β-catenin signaling in airway differentiation and alveolar tissue repair in COPD respectively.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Recently, WNT/β-catenin signaling has been implicated in tissue injury and the regeneration of COPD. [12][13][14] The activity of WNT/β-catenin signaling was decreased in the alveolar epithelial type II (ATII) cells of COPD patients and an emphysema mice model. 12 Wang et al 13 found that the expression profile of WNT/β-catenin signaling was decreased in the small airway epithelium of COPD patients and smokers, suggesting its important role in airway epithelium differentiation.…”

mentioning

confidence: 99%

“…[12][13][14] The activity of WNT/β-catenin signaling was decreased in the alveolar epithelial type II (ATII) cells of COPD patients and an emphysema mice model. 12 Wang et al 13 found that the expression profile of WNT/β-catenin signaling was decreased in the small airway epithelium of COPD patients and smokers, suggesting its important role in airway epithelium differentiation. In addition, TGF-β1-induced WNT/β-catenin signaling activation was enhanced in the lung fibroblasts of COPD subjects, indicating a role for WNT/β-catenin signaling in the fibroblast phenotype and extracellular matrix (ECM) production.…”

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confidence: 99%

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WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

Guo

Wang

et al. 2016

Laboratory Investigation

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The mechanisms of WNT/β-catenin signaling involved in airway inflammation of chronic obstructive pulmonary disease (COPD) remain unknown, although recent observations have suggested an important contribution of the pathway in pulmonary parenchymal tissue repair and airway epithelium differentiation. We investigated the role of WNT/β-catenin signaling in cigarette smoke (CS)-related airway inflammation using patient lung tissues, human bronchial epithelial cells (16HBECs), and mouse models. Reduced activity of WNT/β-catenin signaling was observed in the airway epithelium of smokers with or without COPD. The mRNA expression of WNT transcription factor TCF4 negatively correlated with the pack year. The mRNA levels of WNT receptor FZD4 negatively correlated with the mRNA levels of IL-1β. CS exposure decreased the activity of WNT/β-catenin signaling in both 16HBECs and mice. In vitro studies demonstrated the upregulation of inflammatory cytokines TNF-α and IL-1β secretion induced by CS extract (CSE) could be attenuated by β-catenin activator SB216763 and be exacerbated by β-catenin small-interfering RNA (siRNA), respectively. Furthermore, the decrease in the expression of peroxisome proliferator-activated receptor (PPARδ) induced by CSE stimulation could be rescued by SB216763. SB216763 also attenuated the upregulation of phosphorylated p38 mitogen-activated protein kinase (MAPK) stimulated by CSE. Both PPARδ agonist and p38 MAPK inhibitor could suppress the TNF-α and IL-1β release induced by CSE treatment. In addition, PPARδ activation could abolish β-catenin siRNA-mediated aggravation of phosphorylated p38 MAPK in response to CSE. Finally, SB216763 treatment significantly ameliorated peribronchial inflammatory cell infiltration, leukocyte influx, and the release of TNF-α and IL-1β in the bronchoalveolar lavage fluid of CS-exposed mice. Taken together, our findings indicate that the reduced activity of WNT/β-catenin signaling induced by CS may promote inflammatory cytokine production in airway epithelium and have an essential role in airway inflammation in COPD by PPARδ/p38 MAPK pathway.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

Guo

Wang

et al. 2016

Laboratory Investigation

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“…Thus, the present study is in line with these reports, confirming that aberrant activation of Wnt/β-catenin signaling exists in cigarette smoke-associated airway injury and is responsible for cell proliferation and tissue remodeling at the late stage of injury in response to CSE stimuli. However, one report has contradicted these studies, suggesting that smoking downregulates the Wnt/β-catenin pathway in the human airway epithelium and contributes to the dysregulation of airway epithelium differentiation observed in smoking-related airway disorders (24).…”

Section: Discussionmentioning

confidence: 99%

RNA-binding motif protein 5 negatively regulates the activity of Wnt/β-catenin signaling in cigarette smoke-induced alveolar epithelial injury

Hao

et al. 2015

Oncology Reports

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Abstract. Cigarette smoking is closely associated with various respiratory diseases. Oxidants and carcinogens in cigarettes are reported to induce various airway epithelial injuries. However, the underlying mechanisms remain unclear. The aims of the present study were to determine the involvement of RNA-binding motif protein 5 (RBM5) and Wnt/β-catenin signaling in cigarette smoke-induced alveolar epithelial injury, as well as the interaction between both. A549 cells were treated with cigarette smoke extract (CSE). The MTT assay was used to assess the effects of CSE on cell viability. The levels of RBM5 and Wnt/β-catenin/GSK3β were detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. A luciferase assay was used to assess the activity of β-catenin/T-cell factor (TCF) signaling. The results revealed that CSE inhibited A549 cell viability in both a dose-and time-dependent manner. Cytosolic and nuclear β-catenin levels were significantly increased following CSE treatment, compared with those in the control cells (P<0.05). The luciferase activity in CSE-exposed cells transfected with the TCF luciferase reporter wild-type plasmid (pGL3-OT) was significantly greater than that in cells without CSE exposure (33,167±3,085 vs. 19,978±1,916, respectively, P<0.05). Both the mRNA and protein levels of RBM5 in the CSE-treated cells were significantly reduced compared to the levels in the controls (all P<0.05). The overexpression of RBM5 inhibited Wnt/β-catenin signaling in the A549 cells, while silencing of RBM5 enhanced Wnt/β-catenin signaling. The β-catenin/TCF signaling inhibitor ICG-001 had no apparent effect on the RBM5 levels. Downregulation of RBM5 and activation of Wnt/β-catenin signaling are involved in CSE-induced alveolar epithelial injury. RBM5 acts as an upstream molecule that negatively regulates the activity of Wnt/β-catenin signaling.

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“…The Wnt pathway has been associated with normal lung development and homeostasis as well as chronic lung diseases such as fibrosis and asthma (Konigshoff et al, 2010;Van et al, 2008). However, there are contradictory findings indicating that the Wnt pathway is activated or down-regulated by cigarette smoke in bronchial epithelial cells (Lemjabbar-Alaoui et al, 2006;Wang et al, 2011). Wnt inhibitory factor 1 (Wif1), an extracellular antagonist that acts by binding to Wnt ligands, is a frequent target for epigenetic silencing in various human cancers (Ying et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Wif1 Hypermethylation as Unfavorable Prognosis of Non-Small Cell Lung Cancers with EGFR Mutation

Lee

Park

Kim

2013

Molecules and Cells

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Lung cancer is a leading cause of cancer-related mortality across the world and tobacco smoking is the major risk factor. The Wnt signaling pathway is known to be involved in smoke-induced tumorigenesis in the lung. Promoter hypermethylation of Wnt inhibitory factor 1 (Wif1) has become a common event in a number of human tumors. Using a methylation-specific PCR, hypermethylation of the Wif1 gene promoter was evaluated in 139 primary nonsmall cell lung cancers (NSCLCs) and its correlation with clinicopathological and prognostic parameters was evaluated. Methylation of Wif1 was observed in 47.5% and 20.9% of neoplastic and adjacent normal lung tissues, respectively. Its methylation rate tended to be higher in stage I than stages II-IIIA. Results of Kaplan-Meier analysis showed no significant difference in overall survival according to Wif1 methylation status. However, Wif1 methylation showed an association with unfavorable prognosis of adenocarcinoma (AC) patients with EGFR mutation. According to our current findings, Wif1 promoter methylation is an early, frequent event as an epigenetic field manner and could be considered as a useful prognostic marker for AC patients with EGFR mutation. Further investigation into the therapeutic potential of this finding is warranted.

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Down-Regulation of the Canonical Wnt β-Catenin Pathway in the Airway Epithelium of Healthy Smokers and Smokers with COPD

Cited by 91 publications

References 73 publications

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

RNA-binding motif protein 5 negatively regulates the activity of Wnt/β-catenin signaling in cigarette smoke-induced alveolar epithelial injury

Wif1 Hypermethylation as Unfavorable Prognosis of Non-Small Cell Lung Cancers with EGFR Mutation

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