Increased expression of TROP2 in airway basal cells potentially contributes to airway remodeling in chronic obstructive pulmonary disease

Abstract

BackgroundThe airway epithelium of chronic obstructive pulmonary disease (COPD) patients undergoes aberrant repair and remodeling after repetitive injury following exposure to environmental factors. Abnormal airway regeneration observed in COPD is thought to originate in the stem/progenitor cells of the airway epithelium, the basal cells (BCs). However, the molecular mechanisms underlying these changes remain unknown. Here, trophoblast cell surface antigen 2 (TROP2), a protein implicated in the regulation of stem cell activity, was examined in lung tissue samples from COPD patients.MethodsThe expression of TROP2 and hyperplasia index Ki67 was assessed in lung epithelium specimens from non-smokers (n = 24), smokers (n = 24) and smokers with COPD (n = 24). Primary airway BCs were isolated by bronchoscopy from healthy individuals and COPD patients and subsequently transfected with pcDNA3.1-TROP2 or siRNA sequence in vitro. The functional consequences of TROP2 overexpression in BCs were explored.ResultsImmunohistochemistry and immunofluorescence revealed increased TROP2 expression in airway BCs in smokers with COPD compared to nonsmokers and smokers without COPD, and staining was highly localized to hyperplastic regions containing Ki67 positive cells. TROP2 expression was also inversely correlated with airflow limitation in patients with COPD (r = −0.53, P < 0.01). pcDNA3.1-TROP2-BCs in vitro exhibited improved proliferation with activation of ERK1/2 phosphorylation signaling pathway. In parallel, changes in vimentin and E-cadherin in pcDNA3.1-TROP2-BCs were consistent with an epithelial-mesenchymal transition (EMT)-like change, and secretion of inflammatory factors IL-1β, IL-8 and IL-6 was increased. Moreover, down-regulation of TROP2 by siRNA significantly attenuated the proliferation of BCs derived from COPD patients. EMT-like features and cytokine levels of COPD basal cells were also weakened following the down-regulation of TROP2.ConclusionThe results indicate that TROP2 may play a crucial role in COPD by affecting BC function and thus airway remodeling through increased BC hyperplasia, EMT-like change, and introduction of inflammatory molecules into the microenvironment.

Hedgehog signaling in the airway epithelium of patients with chronic obstructive pulmonary disease

“…Here, we showed that airway epithelial thickness, total epithelial cell count, Ki67+ epithelial cells were positively correlated with airway epithelial-specific PTCH1 protein expression in airway epithelial tissue in all subjects. Consistent with our finding, Liu and colleagues showed a progressive and significant increase in proliferation index (Ki67+ cell) in the airway epithelium of patients without and with COPD (moderate severity), respectively 48 . Our data further demonstrated that severe COPD patients have reduced Ki67+ cells in the airway epithelium compared to moderate COPD patients, which is suggestive of cellular exhaustion.…”

The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target

“…It has also been reported that increased expression of TROP-2 in airway basal cells could contribute to proliferation of such cells derived from smokers with chronic obstructive pulmonary disease (COPD) [ 77 ]. TROP-2 basal cells exhibit improved proliferation with activation of the ERK1/2 phosphorylation signaling pathway, and with an EMT-like change, not unlike the effects found in oncology.…”

Trop2: Jack of All Trades, Master of None

“…In patients with chronic obstructive pulmonary disease (COPD), Trop2 expression is significantly increased in airway basal cells, acting as the stem/progenitor cells of airway epithelium [ 32 ]. In vitro, Trop2 promotes proliferation and self-renewal of basal cells and induces an EMT-like phenotype and the release of proinflammatory cytokines.…”