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

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)-alpha, can increase SOD-2 expression in a human lung adenocarcinoma cell line in vitro, indicating that TNF-alpha-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-alpha-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-alpha-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 king adenocarcinoma, both the number of infiltrating CD68(+) macrophages and INF-alpha expression correlated positively with SOD-2 expression, which is related to lymph node metastasis and TNM stage. We collected the conditioned medium from lipopolysaccharideactivated phorbol myristate acetate-induced THP1 (M1) cells to stimulate A549 and H1299 cells and observed that THP1-M1 upregulated SOD-2 by secreting TNF-alpha. Blocking SOD-2 expression significantly inhibited TNF-alpha-induced cell proliferation in A549 and H1299 cells in vitro. Thus, TNF-alpha-mediated lung inflammation can upregulate SOD-2 expression in lung adenocarcinoma, and macrophages contribute to SOD-2 upregulation by secreting TNF-alpha.