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.