The most frequent cause of death by cancer worldwide is lung cancer, and the 5-year survival rate is still very poor for patients with advanced stage. Understanding the crosstalk between the signaling pathways that are involved in disease, especially in metastasis, is crucial to developing new targeted therapies. Toll-like receptors (TLRs) are master regulators of the immune responses, and their dysregulation in lung cancer is linked to immune escape and promotes tumor malignancy by facilitating angiogenesis and proliferation. On the other hand, over-activation of the WNT signaling pathway has been reported in lung cancer and is also associated with tumor metastasis via induction of Epithelial-to-mesenchymal-transition (EMT)-like processes. An interaction between both TLRs and the WNT pathway was discovered recently as it was found that the TLR pathway can be activated by WNT ligands in the tumor microenvironment; however, the implications of such interactions in the context of lung cancer have not been discussed yet. Here, we offer an overview of the interaction of TLR-WNT in the lung and its potential implications and role in the oncogenic process.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease commonly induced by cigarette smoke. The expression of miRNAs can be altered in patients with COPD and could be used as a biomarker. We aimed to identify a panel of miRNAs in bronchoalveolar lavage (BAL) to differentiate COPD patients from smokers and non-smokers with normal lung function. Accordingly, forty-five subjects classified as COPD, smokers, and non-smokers (n = 15 per group) underwent clinical, functional characterization and bronchoscopy with BAL. The mean age of the studied population was 61.61 ± 12.95 years, BMI 25.72 ± 3.82 Kg/m², FEV1/FVC 68.37 ± 12.00%, and FEV1 80.07 ± 23.63% predicted. According to microarray analysis, three miRNAs of the most upregulated were chosen: miR-320c, miR-200c-3p, and miR-449c-5p. These miRNAs were validated by qPCR and were shown to be differently expressed in COPD patients. ROC analysis showed that these three miRNAs together had an area under the curve of 0.89 in differentiating COPD from controls. Moreover, in silico analysis of candidate miRNAs by DIANA-miRPath showed potential involvement in the EGFR and Hippo pathways. These results suggest a specific 3-miRNA signature that could be potentially used as a biomarker to distinguish COPD patients from smokers and non-smoker subjects.

Inhaled corticosteroids (ICS) use is associated with an increased risk of Pseudomonas aeruginosa (PA) infection in patients with COPD. We aimed to evaluate the effects of ICS on alveolar macrophages in response to PA in COPD patients with and without baseline ICS treatment (COPD and COPD + ICS, respectively) as well as smoker and nonsmoker controls. To do so, cells were infected with PA and cotreated with budesonide (BUD) or fluticasone propionate (FLU). The analysis of NF-κB and c-jun activity revealed a significant increase in both factors in response to PA cotreated with BUD/FLU in smokers but not in COPD or COPD + ICS patients when compared with PA infection alone. The expression of Toll-like receptor 2 (TLR2) and the transcription factor c-jun were induced upon PA infection in nonsmokers only. Moreover, in the smoker and COPD groups, there was a significant increase in TLR2 and a decrease in c-jun expression when treated with BUD/FLU after PA infection, which were not observed in COPD + ICS patients. Therefore, the chronic use of ICS seemingly makes the macrophages tolerant to BUD/FLU stimulation compared with those from patients not treated with ICS, promoting an impaired recognition of PA and activity of alveolar macrophages in terms of altered expression of TLR2 and cytokine production, which could explain the increased risk of PA infection in COPD patients under ICS treatment.

COPD is a frequent, chronic disease characterized by chronic airflow limitation due to anomalies of the respiratory and/or alveolar tracts, mostly caused by exposure to tobacco. Moreover, it is the third leading cause of death in the world, in consequence their early detection is very important. Some biomarkers, such as miRNAs, could help to identify early. Recently, our group has identified a different miRNAs panel in bronchoalveolar lavage (BAL) from patients with COPD (PMID:35466228) Aim: create a profile of miRNAs in serum samples that allows the detection of smokers susceptible to suffering from COPD Methods: Serum sample from 26 patients (14 smokers with normal lung function vs 12 COPD) were analysed to validate BAL’s miRNAs of our previous study: miR-200c-3p, miR-449c-5p, miR-320c; and to validate 2 extra serum miRNAs: miR-210-3p, miR-500a-3p Results: Median age of population was 60±14 years and IMC 26.3±3.7kg/m2. COPD group presented airflow obstruction (FEV1/FVC 55±77%, FEV1 59±19%), unlike smoker group which airflow was normal (FEV1/FVC 77±5%, FEV1 95±179%, p<0.01). In previous study we observed that miRNAs (miR-200c-3p, miR-449c-5p, miR-320c) were up-regulated in BAL from COPD patients, but interestingly in serum miR-200c-3p and miR-320c were down-regulated (p<0.05) in same patients vs smokers and miR-449c-5p was not detected. Serum miRNAs, miR-210-3p and miR-500a-3p, were down- and up-regulated respectively (p<0.05) in COPD group vs smokers Conclusion: Expression of serum miRNAs (miR-200c-3p, miR-320c, miR-210-3p y miR-500a-3p) is different in COPD vs smokers. Moreover, the regulation of miRNAs varies depending on its origin, therefore the choice of type of sample to analyzed is very important