TNF-α-mediated molecular switching links COPD to lung cancer: Integrated in silico and in vivo study of oxidative...

Chronic Obstructive Pulmonary Disease (COPD) and lung cancer (LC), both predominantly linked to smoking, exhibit a poorly understood relationship. Current hypotheses suggest that oxidative stress and sustained inflammation induced by cigarette smoke create a favourable environment for the development of both diseases. Repeated cycles of injury and repair seen in COPD may also contribute to the onset of Tumorigenesis. This study aims to unravel the molecular mechanisms underlying the transition from COPD to LC through a combination of in silico analyses and animal experiments. In silico study included a total of 18 BioProjects for Non-small cell lung cancer (NSCLC) and 7 BioProjects for COPD derived from the National Center for Biotechnology Information-Sequence Read Archive (NCBI-SRA). The differential gene expression analysis, enriched pathway analysis and network analysis were performed using the patients' transcriptomic Next-generation sequencing (NGS) data from both diseases. The study suggested that the Tumor Necrosis Factor (TNF), a pro-inflammatory cytokine, as a potential link between COPD and NSCLC. In vivo experiments were performed with vitamin C-deficient guinea pigs exposed to para-benzoquinone (p-BQ), a component of cigarette smoke and quinone pollution that causes emphysematous damage, while lower doses potentially promote cellular proliferation, making it a good animal model. Histological analyses and immune-detection-based protein analyses reveal a heterogeneous distribution of p-BQ-induced oxidative stress, thereby creating distinct inflammatory states simultaneously. Biphasic activation of TNF-α plays a dual role, showing two opposing phenomena in different phases: acute, with apoptosis and chronic, with proliferation, by activating Caspase 8 and NF-κB, respectively. Gradual remodeling of tissue remodeling sheds light on pre-malignant changes in the chronic phase. As COPD and lung cancer co-exist clinically, this observation potentially contributes to the development of targeted therapies for patients with both diseases.