Local immunosuppressive microenvironment enhances migration of melanoma cells to lungs in DJ-1 knockout mice

PLoS One. 2015 Feb 23;10(2):e0115827. doi: 10.1371/journal.pone.0115827. eCollection 2015.

Abstract

DJ-1 is an oncoprotein that promotes survival of cancer cells through anti-apoptosis. However, DJ-1 also plays a role in regulating IL-1β expression, and whether inflammatory microenvironment built by dysregulated DJ-1 affects cancer progression is still unclear. This study thus aimed to compare the metastatic abilities of melanoma cells in wild-type (WT) and DJ-1 knockout (KO) mice, and to check whether inflammatory microenvironment built in DJ-1 KO mice plays a role in migration of cancer cells to lungs. First, B16F10 melanoma cells (at 6 × 10(4)) were injected into the femoral vein of mice, and formation of lung nodules, levels of lung IL-1β and serum cytokines, and accumulation of myeloid-derived suppressor cells (MDSCs) were compared between WT and DJ-1 KO mice. Second, the cancer-bearing mice were treated with an interleukin-1 beta (IL-1β) neutralizing antibody to see whether IL-1β is involved in the cancer migration. Finally, cultured RAW 264.7 macrophage and B16F10 melanoma cells were respectively treated with DJ-1 shRNA and recombinant IL-1β to explore underlying molecular mechanisms. Our results showed that IL-1β enhanced survival and colony formation of cultured melanoma cells, and that IL-1β levels were elevated both in DJ-1 KO mice and in cultured macrophage cells with DJ-1 knockdown. The elevated IL-1β correlated with higher accumulation of immunosuppressive MDSCs and formation of melanoma module in the lung of DJ-1 KO mice, and both can be decreased by treating mice with IL-1β neutralizing antibodies. Taken together, these results indicate that immunosuppressive tissue microenvironment built in DJ-1 KO mice can enhance lung migration of cancer, and IL-1β plays an important role in promoting the cancer migration.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement*
  • Cellular Microenvironment / immunology*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / secondary
  • Lymphocytes / immunology
  • Melanoma / immunology
  • Melanoma / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / immunology
  • Myeloid Cells / physiology
  • Neoplasm Invasiveness
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Peroxiredoxins / genetics
  • Peroxiredoxins / metabolism*
  • Protein Deglycase DJ-1

Substances

  • Interleukin-1beta
  • Oncogene Proteins
  • Peroxiredoxins
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1

Grants and funding

The study was financially supported by the grant MOST 102-2321-B-002-016 from the Ministry of Science and Technology, Taiwan, R.O.C. to H.H.L. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.