Role of BCL3 dysregulation and LPHN1 in the transition from chronic inflammation in severe asthma to lung cancer

Increased lung cancer risk in asthma patients has been reported, yet the molecular mechanism linking chronic airway inflammation to malignant transformation remains unclear. BCL3 is an atypical member of the Inhibitor of κB family. Transcriptomic studies have reported elevated BCL3 expression in both severe asthma and lung tumor tissues. This study aims to investigate whether BCL3 dysregulation contributes to the transition from chronic inflammation in severe asthma to malignant transformation in the lung. BCL3 was overexpressed or silenced in asthmatic bronchial epithelial cells and lung adenocarcinoma cells. Cell proliferation, apoptosis, and NF-κB activity were assessed. Transcriptomic profiling identified BCL3-regulated genes and pathways. BCL3 overexpression enhanced proliferation and reduced apoptosis in epithelial cells, while its silencing in lung cancer cells produced the opposite effect. BCL3 overexpression reduced NF-κB-responsive reporter activity, whereas BCL3 silencing increased it. Transcriptomic analysis revealed enrichment of GPCR signaling, receptor tyrosine kinase signaling, and immune response pathways. LPHN1, a GPCR, was the only transcript consistently associated with BCL3 across all models. LPHN1 has previously been reported as a prognostic biomarker in NSCLC and as a potential bronchodilator target in asthma. Together, these findings highlight BCL3 dysregulation as a potential contributor to altered epithelial proliferation and survival and identify LPHN1 as a BCL3-associated transcript, providing new insight into molecular changes that may accompany the transition from chronic airway inflammation to lung cancer.