Exploring the role of proteolysis in Extracellular Matrix remodeling: Links to Chronic Obstructive Pulmonary Disease and Lung Cancer

Abstract

Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are two complex disorders, currently representing the 4th cause of death and the most lethal cancer in Western countries, respectively. A mechanistic link between COPD and LC has been proposed due to an overlap of risk factors of both diseases, where uncontrolled proteolysis may be a critical event in their progress and outcomes. The activity of proteases, their substrates and inhibitors have a significant impact in the extracellular matrix (ECM) remodeling, which may ultimately lead to the development of COPD and LC. Despite the identification of several susceptibility factors in both diseases, there is still many aspects of their pathogenesis that require further elucidation. To address this issue, for our study, we selected 73 proteolysis genes, based on their roles in ECM remodeling, lung expression and/or presence in lung samples and former reports by Genome Wide Association Studies. In a first analysis, we took benefit of The Cancer Genome Atlas on-line database regarding clinical, epidemiological and mutational (somatic and germline) information for two common LC subtypes (adenocarcinoma and squamous cell carcinoma). We found that somatic mutability differs from germline trends and between the two LC subtypes, possibly affecting ECM in distinct ways. Then, we screened by means of PCR-based and Sanger sequencing techniques SERPINB3/B4 and CTSG genes, in a small cohort of COPD and LC patients from which blood and bronchoalveolar lavage fluid samples were collected. Even though, we could not detect any somatic mutation in our sample, for SERPINB3 we detect a considerable number of low-frequency variants in COPD cases in particular, suggesting a misfunction of this gene as a possible genetic risk factor for lung disease. Additional studies in larger cohorts of patients and controls are necessary to confirm this hypothesis.