RRC ID 52635
Author Itoh H, Kadomatsu T, Tanoue H, Yugami M, Miyata K, Endo M, Morinaga J, Kobayashi E, Miyamoto T, Kurahashi R, Terada K, Mizuta H, Oike Y.
Title TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma.
Journal Oncogene
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.
Volume 37(22)
Pages 2903-2920
Published 2018-5-1
DOI 10.1038/s41388-018-0160-0
PII 10.1038/s41388-018-0160-0
PMID 29515232
MeSH Animals Bone Neoplasms / genetics Bone Neoplasms / metabolism Bone Neoplasms / pathology* Cell Line, Tumor DNA Methylation* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Epigenesis, Genetic Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Humans Intercellular Adhesion Molecule-1 / genetics Interleukin-6 / genetics* Interleukin-6 / metabolism Lung Neoplasms / genetics Lung Neoplasms / metabolism Lung Neoplasms / pathology* Lung Neoplasms / secondary* MAP Kinase Signaling System Mice Neoplasm Transplantation Osteosarcoma / genetics Osteosarcoma / metabolism Osteosarcoma / pathology* Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism* Tumor Microenvironment Up-Regulation
IF 7.971
Times Cited 15
Human and Animal Cells KUM10(RCB2295)