Related Experiment Video
Updated: Mar 19, 2026
Isolation of Mouse Respiratory Epithelial Cells and Exposure to Experimental Cigarette Smoke at Air Liquid Interface
Published on: February 21, 2011
Prostacyclin reverses the cigarette smoke-induced decrease in pulmonary Frizzled 9 expression through miR-31
M A Tennis1, M L New1, D G McArthur2
1University of Colorado Denver, Aurora, Colorado, USA.
Abstract:
Half of lung cancers are diagnosed in former smokers, leading to a significant treatment burden in this population. Chemoprevention in former smokers using the prostacyclin analogue iloprost reduces endobronchial dysplasia, a premalignant lung lesion. Iloprost requires the presence of the WNT receptor Frizzled 9 (Fzd9) for inhibition of transformed growth in vitro. To investigate the relationship between iloprost, cigarette smoke, and Fzd9 expression, we used human samples, mouse models, and in vitro studies. Fzd9 expression was low in human lung tumors and in progressive dysplasias. In mouse models and in vitro studies, tobacco smoke carcinogens reduced expression of Fzd9 while prostacyclin maintained or increased expression. Expression of miR-31 repressed Fzd9 expression, which was abrogated by prostacyclin. We propose a model where cigarette smoke exposure increases miR-31 expression, which leads to decreased Fzd9 expression and prevents response to iloprost. When smoke is removed miR-31 is reduced, prostacyclin can increase Fzd9 expression, and progression of dysplasia is inhibited. Fzd9 and miR-31 are candidate biomarkers for precision application of iloprost and monitoring of treatment progress. As we continue to investigate the mechanisms of prostacyclin chemoprevention and identify biomarkers for its use, we will facilitate clinical trials and speed implementation of this valuable prevention approach.
Insights
Former smokers with lung cancer can benefit from iloprost chemoprevention. This treatment requires Frizzled 9 (Fzd9) expression, which is reduced by smoking via miR-31, but restored by prostacyclin.
Area of Science:
- Oncology
- Molecular Biology
- Pulmonology
Background:
- Lung cancer is frequently diagnosed in former smokers, posing a significant clinical challenge.
- Endobronchial dysplasia, a precancerous lung lesion, is prevalent in this population.
- Prostacyclin analogue iloprost shows promise for chemoprevention in former smokers.
Purpose of the Study:
- To investigate the interplay between cigarette smoke, Fzd9 expression, and iloprost efficacy.
- To elucidate the molecular mechanisms underlying iloprost's chemopreventive action.
- To identify potential biomarkers for iloprost therapy in former smokers.
Main Methods:
- Analysis of human lung tumor and dysplasia samples.
- In vivo studies using mouse models exposed to tobacco smoke.
- In vitro experiments assessing gene expression and cellular responses.
- Investigated the role of microRNA-31 (miR-31) in regulating Fzd9.
Main Results:
- Fzd9 expression was found to be low in human lung tumors and progressive dysplasias.
- Tobacco smoke carcinogens decreased Fzd9 expression in mouse models and in vitro.
- Prostacyclin treatment maintained or increased Fzd9 expression.
- miR-31 was identified as a repressor of Fzd9, an effect reversed by prostacyclin.
- A model is proposed where smoking increases miR-31, reducing Fzd9 and iloprost response.
Conclusions:
- Cigarette smoke downregulates Fzd9 via miR-31, hindering iloprost efficacy.
- Cessation of smoking and prostacyclin treatment can restore Fzd9 expression.
- Fzd9 and miR-31 are potential biomarkers for guiding iloprost chemoprevention.
- Understanding these mechanisms can accelerate clinical trials and implementation of iloprost therapy.
Related Concept Videos
01:23Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...
01:20Chronic Obstructive Pulmonary Disease-II: Pathophysiology
Chronic Inflammation