TNF‐α‐dependent lung inflammation upregulates superoxide dismutase‐2 to promote tumor cell proliferation in lung adenocarcinoma

Abstract Manganese superoxide dismutase (SOD‐2), an important primary antioxidant enzyme located in mitochondria, plays a critical role in tumor progression. Reportedly, the proinflammatory cytokine, tumor necrosis factor (TNF)‐α, can increase SOD‐2 expression in a human lung adenocarcinoma cell line in vitro, indicating that TNF‐α‐mediated inflammation may regulate SOD‐2 expression, which may be related to cancer promotion. Using a urethane‐induced inflammation‐driven lung adenocarcinoma (IDLA) mice model, we investigated whether and how TNF‐α‐mediated inflammation upregulated SOD‐2 expression in lung adenocarcinoma. Our results showed that SOD‐2 was mostly expressed on surfactant protein‐C + AT‐II cells (alveolar type II cell) and tumor cells in IDLA mice, which were surrounded by CD68 + macrophages. Blocking TNF‐α‐dependent inflammation downregulated SOD‐2 expression in inflamed lung tissues at the protumor stage and also inhibited SOD‐2 expression in tumor cells in the IDLA model. In human lung adenocarcinoma, both the number of infiltrating CD68 + macrophages and TNF‐α expression correlated positively with SOD‐2 expression, which is related to lymph node metastasis and TNM stage. We collected the conditioned medium from lipopolysaccharide‐activated phorbol myristate acetate‐induced THP1 (M1) cells to stimulate A549 and H1299 cells and observed that THP1‐M1 upregulated SOD‐2 by secreting TNF‐α. Blocking SOD‐2 expression significantly inhibited TNF‐α‐induced cell proliferation in A549 and H1299 cells in vitro. Thus, TNF‐α‐mediated lung inflammation can upregulate SOD‐2 expression in lung adenocarcinoma, and macrophages contribute to SOD‐2 upregulation by secreting TNF‐α.