Reference - Detail
|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.|
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.
|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|
|Human and Animal Cells||KUM10(RCB2295)|