Inflammation-mediated SOD-2 upregulation contributes to epithelial-mesenchymal transition and migration of tumor cells in aflatoxin G1-induced lung adenocarcinoma

Sci Rep. 2017 Aug 11;7(1):7953. doi: 10.1038/s41598-017-08537-2.

Abstract

Tumor-associated inflammation plays a critical role in facilitating tumor growth, invasion and metastasis. Our previous study showed Aflatoxin G1 (AFG1) could induce lung adenocarcinoma in mice. Chronic lung inflammation associated with superoxide dismutase (SOD)-2 upregulation was found in the lung carcinogenesis. However, it is unclear whether tumor-associated inflammation mediates SOD-2 to contribute to cell invasion in AFG1-induced lung adenocarcinoma. Here, we found increased SOD-2 expression associated with vimentin, α-SMA, Twist1, and MMP upregulation in AFG1-induced lung adenocarcinoma. Tumor-associated inflammatory microenvironment was also elicited, which may be related to SOD-2 upregulation and EMT in cancer cells. To mimic an AFG1-induced tumor-associated inflammatory microenvironment in vitro, we treated A549 cells and human macrophage THP-1 (MΦ-THP-1) cells with AFG1, TNF-α and/or IL-6 respectively. We found AFG1 did not promote SOD-2 expression and EMT in cancer cells, but enhanced TNF-α and SOD-2 expression in MΦ-THP-1 cells. Furthermore, TNF-α could upregulate SOD-2 expression in A549 cells through NF-κB pathway. Blocking of SOD-2 by siRNA partly inhibited TNF-α-mediated E-cadherin and vimentin alteration, and reversed EMT and cell migration in A549 cells. Thus, we suggest that tumor-associated inflammation mediates SOD-2 upregulation through NF-κB pathway, which may contribute to EMT and cell migration in AFG1-induced lung adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Actins / metabolism
  • Adenocarcinoma of Lung / chemically induced
  • Adenocarcinoma of Lung / metabolism*
  • Aflatoxins / toxicity*
  • Animals
  • Cell Movement
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interleukin-6 / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Mice
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Nuclear Proteins / metabolism
  • Signal Transduction
  • Superoxide Dismutase / metabolism*
  • THP-1 Cells
  • Tumor Necrosis Factor-alpha / pharmacology
  • Twist-Related Protein 1 / metabolism
  • Up-Regulation*
  • Vimentin / metabolism

Substances

  • ACTA2 protein, human
  • Actins
  • Aflatoxins
  • Interleukin-6
  • NF-kappa B
  • Nuclear Proteins
  • TWIST1 protein, human
  • Tumor Necrosis Factor-alpha
  • Twist-Related Protein 1
  • VIM protein, human
  • Vimentin
  • aflatoxin G1
  • Superoxide Dismutase
  • superoxide dismutase 2