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 metas...
Gespeichert in:
| Veröffentlicht in: | Oncogene 2018-05, Vol.37 (22), p.2903-2920 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng ; jpn |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2920 |
|---|---|
| container_issue | 22 |
| container_start_page | 2903 |
| container_title | Oncogene |
| container_volume | 37 |
| creator | Itoh, Hitoshi Kadomatsu, Tsuyoshi Tanoue, Hironori Yugami, Masaki Miyata, Keishi Endo, Motoyoshi Morinaga, Jun Kobayashi, Eisuke Miyamoto, Takeshi Kurahashi, Ryoma Terada, Kazutoyo Mizuta, Hiroshi Oike, Yuichi |
| description | 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. |
| doi_str_mv | 10.1038/s41388-018-0160-0 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_2012116905</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A572595671</galeid><sourcerecordid>A572595671</sourcerecordid><originalsourceid>FETCH-LOGICAL-c676t-6638039c7c7f1f82bd8c2726986d31c978c3df79360d12cbc0fd1720423470a3</originalsourceid><addsrcrecordid>eNp1kV9rFDEUxYModq1-AF9kwBdfpt4kM_nzWEqrhQVf9j1kkzs1ZSdZk4zQb2-GbS2KkoTAze8cbu4h5D2FCwpcfS4D5Ur1QNcjoIcXZEMHKfpx1MNLsgE9Qq8ZZ2fkTSn3ACA1sNfkjOmRjq2-IXF3vWO9xyNGj7F2t9tedCH6xdWQYjejD7ai7_YPXf2OXV3mlLs5uJww_gw5xXlVHXOaU8Xy9I7VlrZDaVZdKhVTsdml2b4lryZ7KPju8T4nu5vr3dXXfvvty-3V5bZ3QoraC8EVcO2kkxOdFNt75ZhkQivhOXVaKsf9JDUX4ClzeweTp5LBwPggwfJz8ulk2xr7sWCpZg7F4eFgI6alGAaUUSo0jA39-Bd6n5YcW3ONGiRjimv1TN3ZA5oQp1SzdaupuRwlG_UoJG3UxT-otjy2kaWIU2j1PwT0JGjzLCXjZI45zDY_GApmjdicIjYtYrNGbKBpPjw2vOxbPL8VT5k2gJ2A0p7iHebnH_3f9RdPsq9a</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2047228398</pqid></control><display><type>article</type><title>TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma</title><source>MEDLINE</source><source>Nature</source><source>Alma/SFX Local Collection</source><creator>Itoh, Hitoshi ; Kadomatsu, Tsuyoshi ; Tanoue, Hironori ; Yugami, Masaki ; Miyata, Keishi ; Endo, Motoyoshi ; Morinaga, Jun ; Kobayashi, Eisuke ; Miyamoto, Takeshi ; Kurahashi, Ryoma ; Terada, Kazutoyo ; Mizuta, Hiroshi ; Oike, Yuichi</creator><creatorcontrib>Itoh, Hitoshi ; Kadomatsu, Tsuyoshi ; Tanoue, Hironori ; Yugami, Masaki ; Miyata, Keishi ; Endo, Motoyoshi ; Morinaga, Jun ; Kobayashi, Eisuke ; Miyamoto, Takeshi ; Kurahashi, Ryoma ; Terada, Kazutoyo ; Mizuta, Hiroshi ; Oike, Yuichi</creatorcontrib><description>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.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-018-0160-0</identifier><identifier>PMID: 29515232</identifier><language>eng ; jpn</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/31 ; 13/89 ; 14/5 ; 38/77 ; 631/67/1344 ; 631/67/327 ; 64/60 ; 82/1 ; Animals ; Apoptosis ; Bone cancer ; Bone Neoplasms - genetics ; Bone Neoplasms - metabolism ; Bone Neoplasms - pathology ; Care and treatment ; Cell adhesion ; Cell Biology ; Cell Line, Tumor ; Colonization ; Complications and side effects ; Demethylation ; Deoxyribonucleic acid ; Development and progression ; DNA ; DNA Methylation ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Epigenesis, Genetic ; Epigenetics ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Genetic aspects ; Genotype ; Glycolysis ; Health aspects ; Human Genetics ; Humans ; Hypoxia ; Intercellular adhesion molecule 1 ; Intercellular Adhesion Molecule-1 - genetics ; Interleukin 6 ; Interleukin 6 receptors ; Interleukin-6 - genetics ; Interleukin-6 - metabolism ; Internal Medicine ; Lung cancer ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Lung Neoplasms - secondary ; Lungs ; MAP Kinase Signaling System ; Medicine ; Medicine & Public Health ; Metastases ; Metastasis ; Mice ; Monoclonal antibodies ; Neoplasm Transplantation ; Oncology ; Osteosarcoma ; Osteosarcoma - genetics ; Osteosarcoma - metabolism ; Osteosarcoma - pathology ; Phenotypes ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Sarcoma ; Tumor cells ; Tumor Microenvironment ; Tumors ; Up-Regulation ; Xenografts</subject><ispartof>Oncogene, 2018-05, Vol.37 (22), p.2903-2920</ispartof><rights>Macmillan Publishers Limited, part of Springer Nature 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c676t-6638039c7c7f1f82bd8c2726986d31c978c3df79360d12cbc0fd1720423470a3</citedby><cites>FETCH-LOGICAL-c676t-6638039c7c7f1f82bd8c2726986d31c978c3df79360d12cbc0fd1720423470a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29515232$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Itoh, Hitoshi</creatorcontrib><creatorcontrib>Kadomatsu, Tsuyoshi</creatorcontrib><creatorcontrib>Tanoue, Hironori</creatorcontrib><creatorcontrib>Yugami, Masaki</creatorcontrib><creatorcontrib>Miyata, Keishi</creatorcontrib><creatorcontrib>Endo, Motoyoshi</creatorcontrib><creatorcontrib>Morinaga, Jun</creatorcontrib><creatorcontrib>Kobayashi, Eisuke</creatorcontrib><creatorcontrib>Miyamoto, Takeshi</creatorcontrib><creatorcontrib>Kurahashi, Ryoma</creatorcontrib><creatorcontrib>Terada, Kazutoyo</creatorcontrib><creatorcontrib>Mizuta, Hiroshi</creatorcontrib><creatorcontrib>Oike, Yuichi</creatorcontrib><title>TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>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.</description><subject>13/31</subject><subject>13/89</subject><subject>14/5</subject><subject>38/77</subject><subject>631/67/1344</subject><subject>631/67/327</subject><subject>64/60</subject><subject>82/1</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Bone cancer</subject><subject>Bone Neoplasms - genetics</subject><subject>Bone Neoplasms - metabolism</subject><subject>Bone Neoplasms - pathology</subject><subject>Care and treatment</subject><subject>Cell adhesion</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Colonization</subject><subject>Complications and side effects</subject><subject>Demethylation</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Knockdown Techniques</subject><subject>Genetic aspects</subject><subject>Genotype</subject><subject>Glycolysis</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Intercellular adhesion molecule 1</subject><subject>Intercellular Adhesion Molecule-1 - genetics</subject><subject>Interleukin 6</subject><subject>Interleukin 6 receptors</subject><subject>Interleukin-6 - genetics</subject><subject>Interleukin-6 - metabolism</subject><subject>Internal Medicine</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Lung Neoplasms - secondary</subject><subject>Lungs</subject><subject>MAP Kinase Signaling System</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Monoclonal antibodies</subject><subject>Neoplasm Transplantation</subject><subject>Oncology</subject><subject>Osteosarcoma</subject><subject>Osteosarcoma - genetics</subject><subject>Osteosarcoma - metabolism</subject><subject>Osteosarcoma - pathology</subject><subject>Phenotypes</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Sarcoma</subject><subject>Tumor cells</subject><subject>Tumor Microenvironment</subject><subject>Tumors</subject><subject>Up-Regulation</subject><subject>Xenografts</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kV9rFDEUxYModq1-AF9kwBdfpt4kM_nzWEqrhQVf9j1kkzs1ZSdZk4zQb2-GbS2KkoTAze8cbu4h5D2FCwpcfS4D5Ur1QNcjoIcXZEMHKfpx1MNLsgE9Qq8ZZ2fkTSn3ACA1sNfkjOmRjq2-IXF3vWO9xyNGj7F2t9tedCH6xdWQYjejD7ai7_YPXf2OXV3mlLs5uJww_gw5xXlVHXOaU8Xy9I7VlrZDaVZdKhVTsdml2b4lryZ7KPju8T4nu5vr3dXXfvvty-3V5bZ3QoraC8EVcO2kkxOdFNt75ZhkQivhOXVaKsf9JDUX4ClzeweTp5LBwPggwfJz8ulk2xr7sWCpZg7F4eFgI6alGAaUUSo0jA39-Bd6n5YcW3ONGiRjimv1TN3ZA5oQp1SzdaupuRwlG_UoJG3UxT-otjy2kaWIU2j1PwT0JGjzLCXjZI45zDY_GApmjdicIjYtYrNGbKBpPjw2vOxbPL8VT5k2gJ2A0p7iHebnH_3f9RdPsq9a</recordid><startdate>20180501</startdate><enddate>20180501</enddate><creator>Itoh, Hitoshi</creator><creator>Kadomatsu, Tsuyoshi</creator><creator>Tanoue, Hironori</creator><creator>Yugami, Masaki</creator><creator>Miyata, Keishi</creator><creator>Endo, Motoyoshi</creator><creator>Morinaga, Jun</creator><creator>Kobayashi, Eisuke</creator><creator>Miyamoto, Takeshi</creator><creator>Kurahashi, Ryoma</creator><creator>Terada, Kazutoyo</creator><creator>Mizuta, Hiroshi</creator><creator>Oike, Yuichi</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20180501</creationdate><title>TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma</title><author>Itoh, Hitoshi ; Kadomatsu, Tsuyoshi ; Tanoue, Hironori ; Yugami, Masaki ; Miyata, Keishi ; Endo, Motoyoshi ; Morinaga, Jun ; Kobayashi, Eisuke ; Miyamoto, Takeshi ; Kurahashi, Ryoma ; Terada, Kazutoyo ; Mizuta, Hiroshi ; Oike, Yuichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c676t-6638039c7c7f1f82bd8c2726986d31c978c3df79360d12cbc0fd1720423470a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng ; jpn</language><creationdate>2018</creationdate><topic>13/31</topic><topic>13/89</topic><topic>14/5</topic><topic>38/77</topic><topic>631/67/1344</topic><topic>631/67/327</topic><topic>64/60</topic><topic>82/1</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Bone cancer</topic><topic>Bone Neoplasms - genetics</topic><topic>Bone Neoplasms - metabolism</topic><topic>Bone Neoplasms - pathology</topic><topic>Care and treatment</topic><topic>Cell adhesion</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Colonization</topic><topic>Complications and side effects</topic><topic>Demethylation</topic><topic>Deoxyribonucleic acid</topic><topic>Development and progression</topic><topic>DNA</topic><topic>DNA Methylation</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetics</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Knockdown Techniques</topic><topic>Genetic aspects</topic><topic>Genotype</topic><topic>Glycolysis</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Intercellular adhesion molecule 1</topic><topic>Intercellular Adhesion Molecule-1 - genetics</topic><topic>Interleukin 6</topic><topic>Interleukin 6 receptors</topic><topic>Interleukin-6 - genetics</topic><topic>Interleukin-6 - metabolism</topic><topic>Internal Medicine</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Lung Neoplasms - secondary</topic><topic>Lungs</topic><topic>MAP Kinase Signaling System</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Monoclonal antibodies</topic><topic>Neoplasm Transplantation</topic><topic>Oncology</topic><topic>Osteosarcoma</topic><topic>Osteosarcoma - genetics</topic><topic>Osteosarcoma - metabolism</topic><topic>Osteosarcoma - pathology</topic><topic>Phenotypes</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Sarcoma</topic><topic>Tumor cells</topic><topic>Tumor Microenvironment</topic><topic>Tumors</topic><topic>Up-Regulation</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Itoh, Hitoshi</creatorcontrib><creatorcontrib>Kadomatsu, Tsuyoshi</creatorcontrib><creatorcontrib>Tanoue, Hironori</creatorcontrib><creatorcontrib>Yugami, Masaki</creatorcontrib><creatorcontrib>Miyata, Keishi</creatorcontrib><creatorcontrib>Endo, Motoyoshi</creatorcontrib><creatorcontrib>Morinaga, Jun</creatorcontrib><creatorcontrib>Kobayashi, Eisuke</creatorcontrib><creatorcontrib>Miyamoto, Takeshi</creatorcontrib><creatorcontrib>Kurahashi, Ryoma</creatorcontrib><creatorcontrib>Terada, Kazutoyo</creatorcontrib><creatorcontrib>Mizuta, Hiroshi</creatorcontrib><creatorcontrib>Oike, Yuichi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Itoh, Hitoshi</au><au>Kadomatsu, Tsuyoshi</au><au>Tanoue, Hironori</au><au>Yugami, Masaki</au><au>Miyata, Keishi</au><au>Endo, Motoyoshi</au><au>Morinaga, Jun</au><au>Kobayashi, Eisuke</au><au>Miyamoto, Takeshi</au><au>Kurahashi, Ryoma</au><au>Terada, Kazutoyo</au><au>Mizuta, Hiroshi</au><au>Oike, Yuichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2018-05-01</date><risdate>2018</risdate><volume>37</volume><issue>22</issue><spage>2903</spage><epage>2920</epage><pages>2903-2920</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29515232</pmid><doi>10.1038/s41388-018-0160-0</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2018-05, Vol.37 (22), p.2903-2920 |
| issn | 0950-9232 1476-5594 |
| language | eng ; jpn |
| recordid | cdi_proquest_miscellaneous_2012116905 |
| source | MEDLINE; Nature; Alma/SFX Local Collection |
| subjects | 13/31 13/89 14/5 38/77 631/67/1344 631/67/327 64/60 82/1 Animals Apoptosis Bone cancer Bone Neoplasms - genetics Bone Neoplasms - metabolism Bone Neoplasms - pathology Care and treatment Cell adhesion Cell Biology Cell Line, Tumor Colonization Complications and side effects Demethylation Deoxyribonucleic acid Development and progression DNA DNA Methylation DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Epigenesis, Genetic Epigenetics Gene expression Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Genetic aspects Genotype Glycolysis Health aspects Human Genetics Humans Hypoxia Intercellular adhesion molecule 1 Intercellular Adhesion Molecule-1 - genetics Interleukin 6 Interleukin 6 receptors Interleukin-6 - genetics Interleukin-6 - metabolism Internal Medicine Lung cancer Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - pathology Lung Neoplasms - secondary Lungs MAP Kinase Signaling System Medicine Medicine & Public Health Metastases Metastasis Mice Monoclonal antibodies Neoplasm Transplantation Oncology Osteosarcoma Osteosarcoma - genetics Osteosarcoma - metabolism Osteosarcoma - pathology Phenotypes Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Sarcoma Tumor cells Tumor Microenvironment Tumors Up-Regulation Xenografts |
| title | TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-27T08%3A44%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=TET2-dependent%20IL-6%20induction%20mediated%20by%20the%20tumor%20microenvironment%20promotes%20tumor%20metastasis%20in%20osteosarcoma&rft.jtitle=Oncogene&rft.au=Itoh,%20Hitoshi&rft.date=2018-05-01&rft.volume=37&rft.issue=22&rft.spage=2903&rft.epage=2920&rft.pages=2903-2920&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/s41388-018-0160-0&rft_dat=%3Cgale_proqu%3EA572595671%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2047228398&rft_id=info:pmid/29515232&rft_galeid=A572595671&rfr_iscdi=true |