TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma.

Abstract

The tumor microenvironment promotes epigenetic changes in tumor cells associated with tumor aggressiveness. Here we report that in primary tumor cells, increased interleukin-6 (IL-6) expression brought on by DNA demethylation of its promoter by ten-eleven translocation 2 (TET2) promotes lung metastasis in osteosarcoma (OS). Xenograft experiments show increased IL-6 expression and decreased methylation of its promoter in OS cells after implantation relative to before implantation. In addition, changes in IL-6 methylation and expression seen in OS cells at the primary site were maintained at the metastatic site. TET2 knockdown in OS cells suppressed upregulation of IL-6 and demethylation of its promoter in xenograft tumors and decreased tumor metastasis. We also present evidence showing that tumor cell-derived IL-6 facilitates glycolytic metabolism in tumor cells by activating the MEK/ERK1/2/hypoxia-inducible transcription factor-1α (HIF-1α) pathway and increases lung colonization by OS cells by upregulating expression of intercellular adhesion molecule-1 (ICAM-1), enhancing tumor metastasis. Blocking IL-6 signaling with a humanized monoclonal antibody against the IL-6 receptor reduced lung metastasis and prolonged survival of xenografted mice. These findings suggest that TET2-dependent IL-6 induction enables acquisition of aggressive phenotypes in OS cells via the tumor microenvironment and that blocking IL-6 signaling could be serve as a potential therapy to antagonize metastasis.

• Authors: Hitoshi Itoh, Tsuyoshi Kadomatsu, Hironori Tanoue, Masaki Yugami, Keishi Miyata, Motoyoshi Endo, Jun Morinaga, Eisuke Kobayashi, Takeshi Miyamoto, Ryoma Kurahashi, Kazutoyo Terada, Hiroshi Mizuta, Yuichi Oike
• Journal: Oncogene (Oncogene) Vol. 37 Issue 22 Pg. 2903-2920 (05 2018) ISSN: 1476-5594 [Electronic] England
• PMID: 29515232 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• ICAM1 protein, human
• IL6 protein, human
• Interleukin-6
• Proto-Oncogene Proteins
• Intercellular Adhesion Molecule-1
• Dioxygenases
• TET2 protein, human

Topics

• Animals
• Bone Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• DNA Methylation
• DNA-Binding Proteins (genetics, metabolism)
• Dioxygenases
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Intercellular Adhesion Molecule-1 (genetics)
• Interleukin-6 (genetics, metabolism)
• Lung Neoplasms (genetics, metabolism, pathology, secondary)
• MAP Kinase Signaling System
• Mice
• Neoplasm Transplantation
• Osteosarcoma (genetics, metabolism, pathology)
• Proto-Oncogene Proteins (genetics, metabolism)
• Tumor Microenvironment
• Up-Regulation