{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:01:29Z","timestamp":1753884089427,"version":"3.41.2"},"reference-count":43,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":2329,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,1,1]]},"abstract":"<jats:p>MicroRNAs (miRs) can regulate tumor cell invasion and metastasis in a tumor specific manner. We recently demonstrated that global downregulation of miRNAs after deleting dicer can promote development of distant metastases in a mouse model of primary soft tissue sarcoma (STS). In this study, we identified miRNAs that are differentially downregulated in metastatic STS in both human and mouse, and investigated the role of these miRNAs in metastasis. miRNA-Taqman PCR arrays showed a global downregulation of miRNAs in metastatic human sarcomas. Similar analysis in mouse metastatic sarcomas revealed overlap for several downregulated miRNAs including miR-16, miR-103, miR-146a, miR-223, miR-342 and miR-511. Restoration of these downregulated miRNAs in mouse primary sarcoma cell lines showed that miR-16, but not other downregulated miRNAs, was able to significantly suppress both migration and invasion in vitro, without altering cell proliferation. In addition, orthotopic transplant of a sarcoma cell line stably expressing miR-16 into the muscle of immunocompromised mice revealed that restoration of miR-16 can significantly decrease lung metastasis in vivo. However, no change in the rate of lung metastasis was observed when miR-16 was deleted in mouse primary sarcomas at sarcoma initiation. Taken together, these results indicate that miR-16 can have metastasis suppressing properties both in vitro and in vivo. However, the loss-of-function experiments in autochthonous tumors indicate that loss of miR-16 is not sufficient to promote metastasis in vivo.<\/jats:p>","DOI":"10.1242\/dmm.017897","type":"journal-article","created":{"date-parts":[[2015,6,5]],"date-time":"2015-06-05T00:32:59Z","timestamp":1433464379000},"source":"Crossref","is-referenced-by-count":3,"title":["MicroRNA-16 suppresses metastasis in an orthotopic, but not autochthonous, mouse model of soft tissue sarcoma"],"prefix":"10.1242","author":[{"given":"Mohit","family":"Sachdeva","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melody J.","family":"Whitley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey K.","family":"Mito","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dina C.","family":"Lev","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana M.","family":"Cardona","sequence":"additional","affiliation":[{"name":"Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David G.","family":"Kirsch","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA"},{"name":"Department of Pharmacology & Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","reference":[{"key":"2021042612480495000_DMM017897C1","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/S0092-8674(01)00616-X","article-title":"microRNAs: tiny regulators with great potential","volume":"107","author":"Ambros","year":"2001","journal-title":"Cell"},{"key":"2021042612480495000_DMM017897C2","doi-asserted-by":"publisher","first-page":"5553","DOI":"10.1158\/0008-5472.CAN-08-4277","article-title":"miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer","volume":"69","author":"Bandi","year":"2009","journal-title":"Cancer Res."},{"key":"2021042612480495000_DMM017897C3","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","article-title":"MicroRNAs: genomics, biogenesis, mechanism, and function","volume":"116","author":"Bartel","year":"2004","journal-title":"Cell"},{"key":"2021042612480495000_DMM017897C4","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1038\/nm.1880","article-title":"The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities","volume":"14","author":"Bonci","year":"2008","journal-title":"Nat. Med."},{"key":"2021042612480495000_DMM017897C5","first-page":"1941","article-title":"Soft tissue sarcomas of adults: state of the translational science","volume":"9","author":"Borden","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"2021042612480495000_DMM017897C6","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1002\/jcp.20282","article-title":"miR-15a and miR-16-1 down-regulation in pituitary adenomas","volume":"204","author":"Bottoni","year":"2005","journal-title":"J. Cell. Physiol."},{"key":"2021042612480495000_DMM017897C7","first-page":"941","article-title":"Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma","volume":"56","author":"Brizel","year":"1996","journal-title":"Cancer Res."},{"key":"2021042612480495000_DMM017897C8","doi-asserted-by":"publisher","first-page":"15524","DOI":"10.1073\/pnas.242606799","article-title":"Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia","volume":"99","author":"Calin","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042612480495000_DMM017897C9","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/ncb2672","article-title":"GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression","volume":"15","author":"Chou","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"2021042612480495000_DMM017897C10","doi-asserted-by":"publisher","first-page":"1882","DOI":"10.1038\/leu.2011.168","article-title":"Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas","volume":"25","author":"Dejean","year":"2011","journal-title":"Leukemia"},{"key":"2021042612480495000_DMM017897C11","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1158\/2159-8290.CD-13-0118","article-title":"Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis","volume":"3","author":"Eisinger-Mathason","year":"2013","journal-title":"Cancer Discov."},{"key":"2021042612480495000_DMM017897C12","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/nrc1840","article-title":"Oncomirs - microRNAs with a role in cancer","volume":"6","author":"Esquela-Kerscher","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"2021042612480495000_DMM017897C13","doi-asserted-by":"publisher","first-page":"6426","DOI":"10.1021\/ac050923i","article-title":"Orthogonality of separation in two-dimensional liquid chromatography","volume":"77","author":"Gilar","year":"2005","journal-title":"Anal. Chem."},{"key":"2021042612480495000_DMM017897C14","doi-asserted-by":"publisher","first-page":"1694","DOI":"10.1002\/jssc.200500116","article-title":"Two-dimensional separation of peptides using RP-RP-HPLC system with different pH in first and second separation dimensions","volume":"28","author":"Gilar","year":"2005","journal-title":"J. Sep. Sci."},{"key":"2021042612480495000_DMM017897C15","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1158\/1541-7786.MCR-14-0249","article-title":"Relocation of CLIC1 promotes tumor cell invasion and colonization of fibrin","volume":"13","author":"Gurski","year":"2014","journal-title":"Mol. Cancer Res"},{"key":"2021042612480495000_DMM017897C16","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1158\/0008-5472.CAN-08-3559","article-title":"Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis","volume":"69","author":"Hurst","year":"2009","journal-title":"Cancer Res."},{"key":"2021042612480495000_DMM017897C17","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1097\/PPO.0b013e318250c001","article-title":"Causes and consequences of microRNA dysregulation","volume":"18","author":"Iorio","year":"2012","journal-title":"Cancer J."},{"key":"2021042612480495000_DMM017897C18","doi-asserted-by":"publisher","first-page":"3243","DOI":"10.1101\/gad.943001","article-title":"Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras","volume":"15","author":"Jackson","year":"2001","journal-title":"Genes Dev."},{"key":"2021042612480495000_DMM017897C19","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.1158\/0008-5472.CAN-11-2663","article-title":"miRNA signatures associate with pathogenesis and progression of osteosarcoma","volume":"72","author":"Jones","year":"2012","journal-title":"Cancer Res."},{"key":"2021042612480495000_DMM017897C43","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/ng747","article-title":"Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer","volume":"29","author":"Jonkers","year":"2001","journal-title":"Nat. Genet."},{"key":"2021042612480495000_DMM017897C20","doi-asserted-by":"publisher","first-page":"e95893","DOI":"10.1371\/journal.pone.0095893","article-title":"Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo","volume":"9","author":"Joshi","year":"2014","journal-title":"PLoS ONE"},{"key":"2021042612480495000_DMM017897C21","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1038\/nm1602","article-title":"A spatially and temporally restricted mouse model of soft tissue sarcoma","volume":"13","author":"Kirsch","year":"2007","journal-title":"Nat. Med."},{"key":"2021042612480495000_DMM017897C22","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.ccr.2009.11.019","article-title":"The DLEU2\/miR-15a\/16\u20131 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia","volume":"17","author":"Klein","year":"2010","journal-title":"Cancer Cell"},{"key":"2021042612480495000_DMM017897C23","doi-asserted-by":"publisher","first-page":"2700","DOI":"10.1101\/gad.1848209","article-title":"Dicer1 functions as a haploinsufficient tumor suppressor","volume":"23","author":"Kumar","year":"2009","journal-title":"Genes Dev."},{"key":"2021042612480495000_DMM017897C24","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1158\/1541-7786.MCR-10-0529","article-title":"miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3","volume":"9","author":"Li","year":"2011","journal-title":"Mol. Cancer Res."},{"key":"2021042612480495000_DMM017897C25","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2021042612480495000_DMM017897C26","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1038\/nature03702","article-title":"MicroRNA expression profiles classify human cancers","volume":"435","author":"Lu","year":"2005","journal-title":"Nature"},{"key":"2021042612480495000_DMM017897C27","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1016\/j.ctrv.2005.07.001","article-title":"The challenge of systematic reviews of diagnostic and staging studies in cancer","volume":"31","author":"Lyman","year":"2005","journal-title":"Cancer Treat. Rev."},{"key":"2021042612480495000_DMM017897C28","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1016\/j.cell.2010.05.017","article-title":"A MicroRNA targeting dicer for metastasis control","volume":"141","author":"Martello","year":"2010","journal-title":"Cell"},{"key":"2021042612480495000_DMM017897C29","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1038\/ncb2684","article-title":"miR-29b moulds the tumour microenvironment to repress metastasis","volume":"15","author":"Melo","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"2021042612480495000_DMM017897C30","doi-asserted-by":"publisher","first-page":"e8075","DOI":"10.1371\/journal.pone.0008075","article-title":"Cross species genomic analysis identifies a mouse model as undifferentiated pleomorphic sarcoma\/malignant fibrous histiocytoma","volume":"4","author":"Mito","year":"2009","journal-title":"PLoS ONE"},{"key":"2021042612480495000_DMM017897C31","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1002\/path.4099","article-title":"Oncogene-dependent control of miRNA biogenesis and metastatic progression in a model of undifferentiated pleomorphic sarcoma","volume":"229","author":"Mito","year":"2013","journal-title":"J. Pathol."},{"key":"2021042612480495000_DMM017897C32","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1038\/nrc2622","article-title":"Metastasis: from dissemination to organ-specific colonization","volume":"9","author":"Nguyen","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"2021042612480495000_DMM017897C33","doi-asserted-by":"publisher","first-page":"3207","DOI":"10.1073\/pnas.0808042106","article-title":"p53 represses c-Myc through induction of the tumor suppressor miR-145","volume":"106","author":"Sachdeva","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042612480495000_DMM017897C34","doi-asserted-by":"publisher","first-page":"6683","DOI":"10.1093\/nar\/gks324","article-title":"Negative regulation of miR-145 by C\/EBP-beta through the Akt pathway in cancer cells","volume":"40","author":"Sachdeva","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2021042612480495000_DMM017897C35","doi-asserted-by":"publisher","first-page":"4305","DOI":"10.1172\/JCI77116","article-title":"MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes","volume":"124","author":"Sachdeva","year":"2014","journal-title":"J. Clin. Invest."},{"key":"2021042612480495000_DMM017897C36","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1002\/(SICI)1097-4652(200003)182:3&lt;311::AID-JCP1&gt;3.0.CO;2-9","article-title":"The Ki-67 protein: from the known and the unknown","volume":"182","author":"Scholzen","year":"2000","journal-title":"J. Cell. Physiol."},{"key":"2021042612480495000_DMM017897C37","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.ccr.2013.12.007","article-title":"CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis","volume":"25","author":"Wang","year":"2014","journal-title":"Cancer Cell"},{"key":"2021042612480495000_DMM017897C38","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/nrclinonc.2010.173","article-title":"Metastamirs: a stepping stone towards improved cancer management","volume":"8","author":"White","year":"2011","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"2021042612480495000_DMM017897C39","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1198\/jasa.2010.tm09415","article-title":"A framework for feature selection in clustering","volume":"105","author":"Witten","year":"2010","journal-title":"J. Am. Stat. Assoc."},{"key":"2021042612480495000_DMM017897C40","doi-asserted-by":"publisher","first-page":"34439","DOI":"10.1074\/jbc.M110.152306","article-title":"MicroRNA-223 regulates cyclin E activity by modulating expression of F-box and WD-40 domain protein 7","volume":"285","author":"Xu","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2021042612480495000_DMM017897C41","doi-asserted-by":"publisher","first-page":"4294","DOI":"10.1038\/onc.2012.432","article-title":"MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1","volume":"32","author":"Yang","year":"2013","journal-title":"Oncogene"},{"key":"2021042612480495000_DMM017897C42","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1210\/me.2012-1006","article-title":"Estrogen promotes prostate cancer cell migration via paracrine release of ENO1 from stromal cells","volume":"26","author":"Yu","year":"2012","journal-title":"Mol. Endocrinol."}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/8\/8\/867\/1868838\/dmm017897.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.017897\/2032373\/dmm_017897.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.017897\/2032373\/dmm_017897.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T21:01:43Z","timestamp":1621371703000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/doi\/10.1242\/dmm.017897\/257017\/MicroRNA-16-suppresses-metastasis-in-an-orthotopic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,1]]},"references-count":43,"URL":"https:\/\/doi.org\/10.1242\/dmm.017897","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"type":"electronic","value":"1754-8411"},{"type":"print","value":"1754-8403"}],"subject":[],"published":{"date-parts":[[2015,1,1]]},"article-number":"dmm.017897"}}