Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation
The imprinted, developmentally regulated H19 long noncoding RNA has been implicated in the pathogenesis of diverse human cancers, but the underlying mechanisms have remained poorly understood. Here, we report that H19 promotes tumor cell migration and invasion by inhibiting let-7, a potent tumor sup...
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| Veröffentlicht in: | Oncogene 2015-06, Vol.34 (23), p.3076-3084 |
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| creator | Yan, L Zhou, J Gao, Y Ghazal, S Lu, L Bellone, S Yang, Y Liu, N Zhao, X Santin, A D Taylor, H Huang, Y |
| description | The imprinted, developmentally regulated H19 long noncoding RNA has been implicated in the pathogenesis of diverse human cancers, but the underlying mechanisms have remained poorly understood. Here, we report that H19 promotes tumor cell migration and invasion by inhibiting let-7, a potent tumor suppressor microRNA that functions to posttranscriptionally suppress the expression of oncogenes that regulate cell growth and motility. We show that H19 depletion impairs, whereas its overexpression enhances the motility and invasiveness of tumor cells. These phenomena occur, at least in part through affecting let-7-mediated regulation of metastasis-promoting genes, including
Hmga2
,
c-Myc
and
Igf2bp3
. This H19/let-7-dependent regulation is recapitulated
in vivo
where co-expressions of oncogenes and H19 exist in both primary human ovarian and endometrial cancers. Furthermore, we provide evidence that the anti-diabetic drug metformin inhibits tumor cell migration and invasion, partly by downregulating H19
via
DNA methylation. Our results reveal a novel mechanism underpinning H19-mediated regulation in metastasis and may explain why in some cases increased let-7 expression unexpectedly correlates with poor prognosis, given the widely accepted role for let-7 as a tumor suppressor. Targeting this newly identified pathway might offer therapeutic opportunities. |
| doi_str_mv | 10.1038/onc.2014.236 |
| format | Article |
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Hmga2
,
c-Myc
and
Igf2bp3
. This H19/let-7-dependent regulation is recapitulated
in vivo
where co-expressions of oncogenes and H19 exist in both primary human ovarian and endometrial cancers. Furthermore, we provide evidence that the anti-diabetic drug metformin inhibits tumor cell migration and invasion, partly by downregulating H19
via
DNA methylation. Our results reveal a novel mechanism underpinning H19-mediated regulation in metastasis and may explain why in some cases increased let-7 expression unexpectedly correlates with poor prognosis, given the widely accepted role for let-7 as a tumor suppressor. Targeting this newly identified pathway might offer therapeutic opportunities.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2014.236</identifier><identifier>PMID: 25088204</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/337/176/1988 ; 631/67 ; 631/80/84/2336 ; 631/80/86 ; Antidiabetics ; Apoptosis ; c-Myc protein ; Carcinogenesis ; Cell adhesion & migration ; Cell Biology ; Cell Line, Tumor ; Cell migration ; Cell Movement ; Deoxyribonucleic acid ; Diabetes mellitus ; DNA ; DNA methylation ; DNA Methylation - drug effects ; Endometrial cancer ; Endometrial Neoplasms - genetics ; Endometrial Neoplasms - metabolism ; Endometrial Neoplasms - pathology ; Endometrium ; Female ; Gene Expression Regulation, Neoplastic ; Gene regulation ; Genetic aspects ; Health aspects ; HEK293 Cells ; Human Genetics ; Humans ; Internal Medicine ; Invasiveness ; Medicine ; Medicine & Public Health ; Metastases ; Metastasis ; Metformin ; Metformin - pharmacology ; MicroRNA ; MicroRNAs ; MicroRNAs - genetics ; MicroRNAs - metabolism ; miRNA ; Motility ; Myc protein ; Neoplasm Invasiveness ; Oncology ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Properties ; RNA, Long Noncoding - genetics ; RNA, Long Noncoding - metabolism ; short-communication ; Signal Transduction ; Transcription (Genetics) ; Transcription factors ; Tumor cells ; Tumor suppressor genes ; Tumors</subject><ispartof>Oncogene, 2015-06, Vol.34 (23), p.3076-3084</ispartof><rights>Macmillan Publishers Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jun 4, 2015</rights><rights>Macmillan Publishers Limited 2015.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c659t-41921d0a4f1135102c70f8e7b7eddbb3956b60d54a396d8c8c56a5bb823e2d5a3</citedby><cites>FETCH-LOGICAL-c659t-41921d0a4f1135102c70f8e7b7eddbb3956b60d54a396d8c8c56a5bb823e2d5a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2014.236$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2014.236$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25088204$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yan, L</creatorcontrib><creatorcontrib>Zhou, J</creatorcontrib><creatorcontrib>Gao, Y</creatorcontrib><creatorcontrib>Ghazal, S</creatorcontrib><creatorcontrib>Lu, L</creatorcontrib><creatorcontrib>Bellone, S</creatorcontrib><creatorcontrib>Yang, Y</creatorcontrib><creatorcontrib>Liu, N</creatorcontrib><creatorcontrib>Zhao, X</creatorcontrib><creatorcontrib>Santin, A D</creatorcontrib><creatorcontrib>Taylor, H</creatorcontrib><creatorcontrib>Huang, Y</creatorcontrib><title>Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>The imprinted, developmentally regulated H19 long noncoding RNA has been implicated in the pathogenesis of diverse human cancers, but the underlying mechanisms have remained poorly understood. Here, we report that H19 promotes tumor cell migration and invasion by inhibiting let-7, a potent tumor suppressor microRNA that functions to posttranscriptionally suppress the expression of oncogenes that regulate cell growth and motility. We show that H19 depletion impairs, whereas its overexpression enhances the motility and invasiveness of tumor cells. These phenomena occur, at least in part through affecting let-7-mediated regulation of metastasis-promoting genes, including
Hmga2
,
c-Myc
and
Igf2bp3
. This H19/let-7-dependent regulation is recapitulated
in vivo
where co-expressions of oncogenes and H19 exist in both primary human ovarian and endometrial cancers. Furthermore, we provide evidence that the anti-diabetic drug metformin inhibits tumor cell migration and invasion, partly by downregulating H19
via
DNA methylation. Our results reveal a novel mechanism underpinning H19-mediated regulation in metastasis and may explain why in some cases increased let-7 expression unexpectedly correlates with poor prognosis, given the widely accepted role for let-7 as a tumor suppressor. Targeting this newly identified pathway might offer therapeutic opportunities.</description><subject>631/337/176/1988</subject><subject>631/67</subject><subject>631/80/84/2336</subject><subject>631/80/86</subject><subject>Antidiabetics</subject><subject>Apoptosis</subject><subject>c-Myc protein</subject><subject>Carcinogenesis</subject><subject>Cell adhesion & migration</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement</subject><subject>Deoxyribonucleic acid</subject><subject>Diabetes mellitus</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Methylation - drug effects</subject><subject>Endometrial cancer</subject><subject>Endometrial Neoplasms - genetics</subject><subject>Endometrial Neoplasms - metabolism</subject><subject>Endometrial Neoplasms - pathology</subject><subject>Endometrium</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene regulation</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>HEK293 Cells</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Invasiveness</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Metformin</subject><subject>Metformin - pharmacology</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><subject>miRNA</subject><subject>Motility</subject><subject>Myc protein</subject><subject>Neoplasm Invasiveness</subject><subject>Oncology</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Properties</subject><subject>RNA, Long Noncoding - genetics</subject><subject>RNA, Long Noncoding - metabolism</subject><subject>short-communication</subject><subject>Signal Transduction</subject><subject>Transcription (Genetics)</subject><subject>Transcription factors</subject><subject>Tumor cells</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkktrFTEYhoMo9ljduZYBNy6c09wvy0OtVigKouuQSTKnKTNJTWaKx1_fDFOlSlESCPnyfJc3vAC8RHCLIJEnKdothohuMeGPwAZRwVvGFH0MNlAx2CpM8BF4VsoVhFAoiJ-CI8yglBjSDTh88ft5MFNIsUl9M81jyo31w9CMYZ_XuImuCfHGlOXSHZrp0jfnSJ0MfmpFY36E0tRt4mT2KYaf3i3Q6Kc-5THENkQ32xp892m3RC8Pa7vn4ElvhuJf3J3H4Nv7s6-n5-3F5w8fT3cXreVMTS1FCiMHDe0RIgxBbAXspRed8M51HVGMdxw6Rg1R3EkrLeOGdZ3ExGPHDDkGb9a61zl9n32Z9BjKotBEn-aikaifJyTn8v8ol5wiiAiq6Ou_0Ks051iFaEwI4khRKP5F1VpMMIHFvVp7M3gdYp-mbOzSWu8okoTiKqZS2weoupwfg03R96HG_0h4uybYnErJvtfXOYwmHzSCerGOrtbRi3XqyLzir-5mnbvRu9_wL69UoF2BUp_i3ud7Yh4qeAsm5MpM</recordid><startdate>20150604</startdate><enddate>20150604</enddate><creator>Yan, L</creator><creator>Zhou, J</creator><creator>Gao, Y</creator><creator>Ghazal, S</creator><creator>Lu, L</creator><creator>Bellone, S</creator><creator>Yang, Y</creator><creator>Liu, N</creator><creator>Zhao, X</creator><creator>Santin, A D</creator><creator>Taylor, H</creator><creator>Huang, Y</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>20150604</creationdate><title>Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation</title><author>Yan, L ; Zhou, J ; Gao, Y ; Ghazal, S ; Lu, L ; Bellone, S ; Yang, Y ; Liu, N ; Zhao, X ; Santin, A D ; Taylor, H ; Huang, Y</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c659t-41921d0a4f1135102c70f8e7b7eddbb3956b60d54a396d8c8c56a5bb823e2d5a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>631/337/176/1988</topic><topic>631/67</topic><topic>631/80/84/2336</topic><topic>631/80/86</topic><topic>Antidiabetics</topic><topic>Apoptosis</topic><topic>c-Myc protein</topic><topic>Carcinogenesis</topic><topic>Cell adhesion & migration</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Movement</topic><topic>Deoxyribonucleic acid</topic><topic>Diabetes mellitus</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>DNA Methylation - drug effects</topic><topic>Endometrial cancer</topic><topic>Endometrial Neoplasms - genetics</topic><topic>Endometrial Neoplasms - metabolism</topic><topic>Endometrial Neoplasms - pathology</topic><topic>Endometrium</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene regulation</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>HEK293 Cells</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Invasiveness</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Metformin</topic><topic>Metformin - pharmacology</topic><topic>MicroRNA</topic><topic>MicroRNAs</topic><topic>MicroRNAs - genetics</topic><topic>MicroRNAs - metabolism</topic><topic>miRNA</topic><topic>Motility</topic><topic>Myc protein</topic><topic>Neoplasm Invasiveness</topic><topic>Oncology</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Properties</topic><topic>RNA, Long Noncoding - genetics</topic><topic>RNA, Long Noncoding - metabolism</topic><topic>short-communication</topic><topic>Signal Transduction</topic><topic>Transcription (Genetics)</topic><topic>Transcription factors</topic><topic>Tumor cells</topic><topic>Tumor suppressor genes</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yan, L</creatorcontrib><creatorcontrib>Zhou, J</creatorcontrib><creatorcontrib>Gao, Y</creatorcontrib><creatorcontrib>Ghazal, S</creatorcontrib><creatorcontrib>Lu, L</creatorcontrib><creatorcontrib>Bellone, S</creatorcontrib><creatorcontrib>Yang, Y</creatorcontrib><creatorcontrib>Liu, N</creatorcontrib><creatorcontrib>Zhao, X</creatorcontrib><creatorcontrib>Santin, A D</creatorcontrib><creatorcontrib>Taylor, H</creatorcontrib><creatorcontrib>Huang, Y</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>Yan, L</au><au>Zhou, J</au><au>Gao, Y</au><au>Ghazal, S</au><au>Lu, L</au><au>Bellone, S</au><au>Yang, Y</au><au>Liu, N</au><au>Zhao, X</au><au>Santin, A D</au><au>Taylor, H</au><au>Huang, Y</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2015-06-04</date><risdate>2015</risdate><volume>34</volume><issue>23</issue><spage>3076</spage><epage>3084</epage><pages>3076-3084</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>The imprinted, developmentally regulated H19 long noncoding RNA has been implicated in the pathogenesis of diverse human cancers, but the underlying mechanisms have remained poorly understood. Here, we report that H19 promotes tumor cell migration and invasion by inhibiting let-7, a potent tumor suppressor microRNA that functions to posttranscriptionally suppress the expression of oncogenes that regulate cell growth and motility. We show that H19 depletion impairs, whereas its overexpression enhances the motility and invasiveness of tumor cells. These phenomena occur, at least in part through affecting let-7-mediated regulation of metastasis-promoting genes, including
Hmga2
,
c-Myc
and
Igf2bp3
. This H19/let-7-dependent regulation is recapitulated
in vivo
where co-expressions of oncogenes and H19 exist in both primary human ovarian and endometrial cancers. Furthermore, we provide evidence that the anti-diabetic drug metformin inhibits tumor cell migration and invasion, partly by downregulating H19
via
DNA methylation. Our results reveal a novel mechanism underpinning H19-mediated regulation in metastasis and may explain why in some cases increased let-7 expression unexpectedly correlates with poor prognosis, given the widely accepted role for let-7 as a tumor suppressor. Targeting this newly identified pathway might offer therapeutic opportunities.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25088204</pmid><doi>10.1038/onc.2014.236</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | 631/337/176/1988 631/67 631/80/84/2336 631/80/86 Antidiabetics Apoptosis c-Myc protein Carcinogenesis Cell adhesion & migration Cell Biology Cell Line, Tumor Cell migration Cell Movement Deoxyribonucleic acid Diabetes mellitus DNA DNA methylation DNA Methylation - drug effects Endometrial cancer Endometrial Neoplasms - genetics Endometrial Neoplasms - metabolism Endometrial Neoplasms - pathology Endometrium Female Gene Expression Regulation, Neoplastic Gene regulation Genetic aspects Health aspects HEK293 Cells Human Genetics Humans Internal Medicine Invasiveness Medicine Medicine & Public Health Metastases Metastasis Metformin Metformin - pharmacology MicroRNA MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism miRNA Motility Myc protein Neoplasm Invasiveness Oncology Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Properties RNA, Long Noncoding - genetics RNA, Long Noncoding - metabolism short-communication Signal Transduction Transcription (Genetics) Transcription factors Tumor cells Tumor suppressor genes Tumors |
| title | Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation |
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