Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-ß-dependent activation of matrix metalloproteases.
Carcinogenesis
; 37(1): 18-29, 2016 Jan.
Article
em En
| MEDLINE
| ID: mdl-26503968
ABSTRACT
Dickkopf-3 (Dkk-3) is a secreted protein whose expression is downregulated in many types of cancer. Endogenous Dkk-3 is required for formation of acini in 3D cultures of prostate epithelial cells, where it inhibits transforming growth factor (TGF)-ß/Smad signaling. Here, we examined the effects of Dkk-3 on the expression and activity of matrix metalloproteases (MMPs), which mediate the effects of TGF-ß on extracellular matrix disassembly during tissue morphogenesis and promote invasion of tumor cells. Silencing of Dkk-3 in prostate epithelial cells resulted in increased expression and enzyme activity of MMP-2 and MMP-9. Inhibition of MMP-9 partially restored normal acinar morphogenesis in Dkk-3-silenced RWPE-1 prostate epithelial cells. In PC3 prostate cancer cells, Dkk-3 inhibited TGF-ß-dependent migration and invasion. Inhibition was mediated by the Dkk-3 C-terminal cysteine-rich domain (Cys2), which also inhibited TGF-ß-induced expression of MMP9 and MMP13. In contrast, Dkk-3, but not Cys2, increased formation of normal acini in Dkk-3-silenced prostate epithelial cells. These observations highlight a role for Dkk-3 in modulating TGF-ß/MMP signals in the prostate, and suggest that the Dkk-3 Cys2 domain can be used as a basis for therapies that target the tumor promoting effects of TGF-ß signaling in advanced prostate cancer.
Texto completo:
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Bases de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Fator de Crescimento Transformador beta
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Metaloproteinase 2 da Matriz
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Metaloproteinase 9 da Matriz
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Peptídeos e Proteínas de Sinalização Intercelular
Limite:
Humans
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Male
Idioma:
En
Revista:
Carcinogenesis
Ano de publicação:
2016
Tipo de documento:
Article