Proliferation Genes Repressed by TGF-β AreDownstream of Slug/Snail2 in Normal Bronchial EpithelialProgenitors and Are Deregulated in COPD

Slug/Snail2 belongs to the Epithelial-Mesenchymal Transition (EMT)-inducing transcription factors that are involved in development and diseases. Slug is also highly expressed in normal adult stem/progenitor cells of several epitheliums, and in such is unique among these transcription factors. By comparing primary bronchial basal cells from normal subjects to those from subjects with Chronic Obstructive Pulmonary Disease (COPD), a respiratory disease in which subjects present many anomalies of their bronchial epithelium and higher levels of Transforming Growth Factor (TGF)-{beta} in their lungs, in an air-liquid interface culture system that allows regenerating a bronchial epithelium similar to the one in vivo, we reveal that Slug has higher expression levels in basal/progenitor cells from COPD when in presence of TGF-{beta} but that it does not repress the epithelial marker E-cadherin either in normal or in COPD cells, even when treated with TGF-{beta}. To investigate Slug role in human primary bronchial basal/progenitor cells we performed loss of function experiments to determine Slug downstream genes and we characterized the impact of TGF-{beta} on these genes. We show that Slug downstream genes are different in normal and COPD subjects. In particular, we identified a set of proliferation-related genes whose expression is decreased by TGF-{beta} when cells are induced to differentiate, and that are among the genes repressed downstream of Slug in normal but not in COPD cells. In COPD the levels of expression of these genes are higher than in normal cells in presence of TGF-{beta}, and they positively correlate with the effect of TGF-{beta} on Slug. Our findings show that Slug is involved in the repression of proliferation genes by TGF-{beta} in normal basal/progenitor cells, but that in contrast, in subjects that present many anomalies in their bronchial epithelium this function of Slug is lost and Slug and proliferation genes are simultaneously but independently regulated by TGF-{beta}.