SO2 derivatives and As co-exposure promote liver cancer metastasis through integrin αvβ3 activation.

Arsenic (As) and sulfur dioxide (SO2) are two environmental pollutants that have been shown to promote the development of human cancer. In recent years, due to increased pollution, humans are often exposed to SO2, in addition to As. Despite the development and implementation of standards for environment and air quality, cases of disease caused by As or SO2 continue to rise alarmingly. It is currently unknown whether simultaneous exposure to As and SO2 results in increased cancer promoting activity. In this study, concentrations of As and SO2 below the limits established by the world health organization (WHO) in force environmental standards (concentrations of As should be lower than 1×10-2 mg/L and SO2 should be lower than 50 μg/m3), were employed to investigate possible, long-term, synergistic effects of As and SO2, by using cell-based assays. We found that co-exposure to these pollutants significantly promotes HepG2 cancer cell migration, while As or SO2 alone have no remarkable effects. Integrins αvβ3 play a key role in this process, as cilengitide, an integrin αvβ3 inhibitor, substantially prevented As and SO2-induced cell migration. MMPs, IL-8, and TGF-β were also involved in the induced cell migration. In summary, combined exposure to As and SO2 promotes integrin-dependent cell migration and may be of relevance for the activation of mechanisms underlying liver cancer progression.