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Título: | Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells |
Autor: | Álvarez-Díaz, S. CSIC ORCID; Valle, Noelia CSIC ORCID CVN; García, José M.; Peña, Cristina; Freije, José M. P.; Quesada, Víctor; Astudillo, Aurora; Bonilla, Félix; López-Otín, Carlos CSIC ORCID; Muñoz Terol, Alberto CSIC ORCID | Fecha de publicación: | ago-2009 | Editor: | American Society for Clinical Investigation | Citación: | Journal of Clinical Investigation 119(8): 2343-2358 (2009) | Resumen: | The 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. | Descripción: | 16 pages, 11 figures. | Versión del editor: | http://dx.doi.org/10.1172/JCI37205 | URI: | http://hdl.handle.net/10261/24884 | DOI: | 10.1172/JCI37205 | ISSN: | 0021-9738 |
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