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dc.contributor.authorPratap, Jitesh
dc.contributor.authorJaved, Amjad
dc.contributor.authorLanguino, Lucia R.
dc.contributor.authorVan Wijnen, Andre J.
dc.contributor.authorStein, Janet L.
dc.contributor.authorStein, Gary S.
dc.contributor.authorLian, Jane B.
dc.date2022-08-11T08:08:47.000
dc.date.accessioned2022-08-23T16:08:22Z
dc.date.available2022-08-23T16:08:22Z
dc.date.issued2005-09-17
dc.date.submitted2008-11-26
dc.identifier.citationMol Cell Biol. 2005 Oct;25(19):8581-91. <a href="http://dx.doi.org/10.1128/MCB.25.19.8581-8591.2005 ">Link to article on publisher's site</a>
dc.identifier.issn0270-7306 (Print)
dc.identifier.doi10.1128/MCB.25.19.8581-8591.2005
dc.identifier.pmid16166639
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32433
dc.description.abstractThe Runx2 (Cbfa1/AML3) transcription factor and matrix metalloproteinase 9 (MMP9) are key regulators of growth plate maturation and bone formation. The genes for both proteins are characteristic markers of breast and prostate cancer cells that metastasize to bone. Here we experimentally addressed the compelling question of whether Runx2 and MMP are functionally linked. By cDNA expression array analysis, we identified MMP9 as a novel downstream target of Runx2. Like that of MMP13, MMP9 expression is nearly depleted in Runx2 mutant mice. Chromatin immunoprecipitation and electrophoretic mobility shift assays revealed the recruitment of Runx2 to the MMP9 promoter. We show by mutational analysis that the Runx2 site mediates transactivation of the MMP9 promoter in osteoblasts (MC3T3-E1) and nonosseous (HeLa) cells. The overexpression of Runx2 by adenovirus delivery in nonmetastatic (MCF-7) and metastatic breast (MDA-MB-231) and prostate (PC3) cancer cell lines significantly increases the endogenous levels of MMP9. The knockdown of Runx2 by RNA interference decreases MMP9 expression, as well as that of other Runx2 target genes, including the genes for MMP13 and vascular endothelial growth factor. Importantly, we have demonstrated using a cell invasion assay that Runx2-regulated MMP9 levels are functionally related to the invasion properties of cancer cells. These results are consistent with Runx2 control of multiple genes that contribute to the metastatic properties of cancer cells and their activity in the bone microenvironment.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16166639&dopt=Abstract">Link to article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1128/MCB.25.19.8581-8591.2005
dc.subject3T3 Cells; Adenoviridae; Animals; Blotting, Western; Bone Neoplasms; Cell Line, Tumor; Cell Nucleus; Chromatin Immunoprecipitation; Core Binding Factor Alpha 1 Subunit; DNA, Complementary; *Gene Expression Regulation, Enzymologic; Hela Cells; Humans; Matrix Metalloproteinase 9; Mice; Mice, Mutant Strains; Models, Biological; Models, Genetic; Neoplasm Invasiveness; Neoplasm Metastasis; Osteoblasts; Promoter Regions (Genetics); RNA; RNA Interference; RNA, Messenger; RNA, Small Interfering; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Trans-Activation (Genetics)
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleThe Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion
dc.typeJournal Article
dc.source.journaltitleMolecular and cellular biology
dc.source.volume25
dc.source.issue19
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/1003
dc.identifier.contextkey673219
html.description.abstract<p>The Runx2 (Cbfa1/AML3) transcription factor and matrix metalloproteinase 9 (MMP9) are key regulators of growth plate maturation and bone formation. The genes for both proteins are characteristic markers of breast and prostate cancer cells that metastasize to bone. Here we experimentally addressed the compelling question of whether Runx2 and MMP are functionally linked. By cDNA expression array analysis, we identified MMP9 as a novel downstream target of Runx2. Like that of MMP13, MMP9 expression is nearly depleted in Runx2 mutant mice. Chromatin immunoprecipitation and electrophoretic mobility shift assays revealed the recruitment of Runx2 to the MMP9 promoter. We show by mutational analysis that the Runx2 site mediates transactivation of the MMP9 promoter in osteoblasts (MC3T3-E1) and nonosseous (HeLa) cells. The overexpression of Runx2 by adenovirus delivery in nonmetastatic (MCF-7) and metastatic breast (MDA-MB-231) and prostate (PC3) cancer cell lines significantly increases the endogenous levels of MMP9. The knockdown of Runx2 by RNA interference decreases MMP9 expression, as well as that of other Runx2 target genes, including the genes for MMP13 and vascular endothelial growth factor. Importantly, we have demonstrated using a cell invasion assay that Runx2-regulated MMP9 levels are functionally related to the invasion properties of cancer cells. These results are consistent with Runx2 control of multiple genes that contribute to the metastatic properties of cancer cells and their activity in the bone microenvironment.</p>
dc.identifier.submissionpathgsbs_sp/1003
dc.contributor.departmentDepartment of Cancer Biology
dc.contributor.departmentDepartment of Cell Biology
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.source.pages8581-91


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