Fig. 1.

Canonical WNT pathway is upregulated in COPD proximal epithelium.

a) Heat map of RNA-seq expression Z-score, computed for all significantly modified genes (fold discovery range < 0•1) in smokers and COPD, as compared with non-smoker controls. These results depict a global WNT activation in COPD, that is more pronounced in very severe disease. The horizontal gap separates upregulated and downregulated targets.

b) Schematized overview of the canonical WNT pathway and its most important components. Green and red-filled rectangles respectively represent significantly up- and downregulated genes in COPD, according to RNA-seq data (dedicated statistical analysis, comparing pooled COPD versus non-smoker controls). Red-framed rectangles (CSNKA1&2, FBXW11, TLE1) point genes whose upregulation does support canonical WNT activation. Interestingly, two of these genes are involved in the phosphorylation and ubiquitination of the β-catenin, and their divergent regulation could be a direct consequence of the increased β-catenin cytosolic pool.

c) The most affected target genes (>2-fold change) in RNA-seq, namely MMP2, MMP7, FZD7, SOX4, as well as CTNNB1, the cardinal factor of canonical WNT, were validated by RT-qPCR in the initial 47 patients series enriched with 21 additional samples

*, **, ***, **** indicate p-values of less than 0•05, 0•01, 0•001, and 0•0001, respectively (analysed using the Kruskal-Wallis test followed by Dunn's post-hoc test). Bars indicate median ± interquartile range. COPD, chronic obstructive pulmonary disease; EMT, epithelial-to-mesenchymal transition; NS, non-smokers; ns, not significant; Smo, smokers.