期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 119, 期 8, 页码 2343-2358出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI37205
关键词
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资金
- Ministerio de Ciencia e Innovacion [SAF2007-60341, SAF2006-00476, ISCIII-RETIC RD06/0020/0009, RD06/0020/0020]
- Comunidad de Madrid [S-GEN-0266/2006]
- European Union [MRTN-CT-2005019496]
The active vitamin D metabolite 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3] has wide but not fully understood antitumor activity. A previous transcriptomic analysis of 1 alpha,25(OH)(2)D-3 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 1 alpha,25(OH)(2)D-3 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/beta-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 antiproliferadve effect of 1 alpha,25(OH)(2)D-3, 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 1 alpha,25(OH)(2)D-3 in colon cancer.
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