Alpha-1 antitrypsin is a player of pleural mesothelial cell transformation

Alpha1-antitrypsin (AAT) is a serum acute-phase protein encoded by the SERPINA1 gene. It is mainly produced by hepatocytes, and it is involved in anti-inflammatory processes. Altered expression of AAT in human cells can hamper proliferation and apoptosis, leading to transformation. In this study, the transforming activity of AAT was investigated in human pleural mesothelial cells (MeT-5A). AAT expression was first investigated in Met-5A and pleural mesothelioma (PM) cell lines of different histotypes, such as epithelioid, biphasic and sarcomatoid, by droplet digital PCR, showing mRNA to be lowest in MeT-5A and highest in the PM cell lines biphasic (MSTO-211H) and sarcomatoid (H2052). To assess AAT role “SERPINA1 gain and loss of function” experiments were performed to assay cell viability, proliferation and migration in normal and PM cell lines. Met- 5A cells overexpressing SERPINA1 resulted in increased cell viability and proliferation compared to non-transfected cells. Conversely, SERPINA1-silenced PM cell lines MSTO-211H and H2052 showed a decrease in both cell viability and cell proliferation compared to non-transfected cells. Cell treatment with staurosporine, a proapoptotic agent, showed caspase 3/7 signaling activation in SERPINA1-silenced PM cell lines MSTO-211H and H2052 compared to non-transfected and to Met- 5A cells overexpressing SERPINA1. Our preliminary data indicate that AAT may play a role in human mesothelial cell transformation, especially in the biphasic and sarcomatoid histotypes, thus representing a potentially novel transforming pathway to be investigated in PM.