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dc.contributor.authorÁlvarez-Díaz, S.-
dc.contributor.authorValle, Noelia-
dc.contributor.authorGarcía, José M.-
dc.contributor.authorPeña, Cristina-
dc.contributor.authorFreije, José M. P.-
dc.contributor.authorQuesada, Víctor-
dc.contributor.authorAstudillo, Aurora-
dc.contributor.authorBonilla, Félix-
dc.contributor.authorLópez-Otín, Carlos-
dc.contributor.authorMuñoz Terol, Alberto-
dc.date.accessioned2010-05-31T12:11:14Z-
dc.date.available2010-05-31T12:11:14Z-
dc.date.issued2009-08-
dc.identifier.citationJournal of Clinical Investigation 119(8): 2343-2358 (2009)en_US
dc.identifier.issn0021-9738-
dc.identifier.urihttp://hdl.handle.net/10261/24884-
dc.description16 pages, 11 figures.en_US
dc.description.abstractThe active vitamin D metabolite 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] has wide but not fully understood antitumor activity. A previous transcriptomic analysis of 1α,25(OH)2D3 action on human colon cancer cells revealed cystatin D (CST5), which encodes an inhibitor of several cysteine proteases of the cathepsin family, as a candidate target gene. Here we report that 1α,25(OH)2D3 induced vitamin D receptor (VDR) binding to, and activation of, the CST5 promoter and increased CST5 RNA and protein levels in human colon cancer cells. In cells lacking endogenous cystatin D, ectopic cystatin D expression inhibited both proliferation in vitro and xenograft tumor growth in vivo. Furthermore, cystatin D inhibited migration and anchorage-independent growth, antagonized the Wnt/β-catenin signaling pathway, and repressed c-MYC expression. Cystatin D repressed expression of the epithelial-mesenchymal transition inducers SNAI1, SNAI2, ZEB1, and ZEB2 and, conversely, induced E-cadherin and other adhesion proteins. CST5 knockdown using shRNA abrogated the antiproliferative effect of 1α,25(OH)2D3, attenuated E-cadherin expression, and increased c-MYC expression. In human colorectal tumors, expression of cystatin D correlated with expression of VDR and E-cadherin, and loss of cystatin D correlated with poor tumor differentiation. Based on these data, we propose that CST5 has tumor suppressor activity that may contribute to the antitumoral action of 1α,25(OH)2D3 in colon cancer.en_US
dc.description.sponsorshipThis work was supported by the Ministerio de Ciencia e Innovación (SAF2007-60341, SAF2006-00476, ISCIII-RETIC RD06/0020/0009, and RD06/0020/0020), Comunidad de Madrid (S-GEN-0266/2006), and the European Union (MRTN-CT-2005-019496, NucSys and Micoenvimet, FP7). The Instituto Universitario de Oncología and Hospital Universitario Central de Asturias tumor bank are supported by Obra Social Cajastur and Acción Transversal del Cáncer–RTICC.en_US
dc.format.extent5990725 bytes-
dc.format.mimetypeapplication/pdf-
dc.language.isoengen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.rightsopenAccessen_US
dc.titleCystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cellsen_US
dc.typeartículoen_US
dc.identifier.doi10.1172/JCI37205-
dc.description.peerreviewedPeer revieweden_US
dc.relation.publisherversionhttp://dx.doi.org/10.1172/JCI37205en_US
dc.identifier.pmid19662683-
dc.type.coarhttp://purl.org/coar/resource_type/c_6501es_ES
item.openairetypeartículo-
item.cerifentitytypePublications-
item.languageiso639-1en-
item.grantfulltextopen-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.fulltextWith Fulltext-
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