Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-β-dependent activation of matrix metalloproteases.
File(s)
Accepted version
Author(s)
Type
Journal Article
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)-β/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-β 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 prostate cancer, Dkk-3 inhibited TGF-β-dependent
migration and invasion. Inhibition was mediated by the Dkk-3 C-terminal cysteine-rich
domain (Cys2), which also inhibited TGF-β-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-β/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-β signaling in advanced prostate
cancer.
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)-β/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-β 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 prostate cancer, Dkk-3 inhibited TGF-β-dependent
migration and invasion. Inhibition was mediated by the Dkk-3 C-terminal cysteine-rich
domain (Cys2), which also inhibited TGF-β-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-β/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-β signaling in advanced prostate
cancer.
Date Issued
2015-10-26
Date Acceptance
2015-10-19
Citation
Carcinogenesis, 2015, 37 (1), pp.18-29
ISSN
1460-2180
Publisher
Oxford University Press (OUP)
Start Page
18
End Page
29
Journal / Book Title
Carcinogenesis
Volume
37
Issue
1
Copyright Statement
This is a pre-copyedited, author-produced PDF of an article accepted for publication in Carcinogenesis following peer review. The version of record Diana Romero, Zainab Al-Shareef, Irantzu Gorroño-Etxebarria, Stephanie Atkins, Frances Turrell, Jyoti Chhetri, Nora Bengoa-Vergniory, Christoph Zenzmaier, Peter Berger, Jonathan Waxman, and Robert Kypta
Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-β-dependent activation of matrix metalloproteases
Carcinogenesis (2016) 37 (1): 18-29 first published online October 26, 2015 is available online at: http://carcin.oxfordjournals.org/content/37/1/18.long
Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-β-dependent activation of matrix metalloproteases
Carcinogenesis (2016) 37 (1): 18-29 first published online October 26, 2015 is available online at: http://carcin.oxfordjournals.org/content/37/1/18.long
Sponsor
Prostate Cancer UK
Rosetrees Trust
Grant Number
WSCC_P43374
A542
Subjects
Dickkopf-3
Metastatic prostate cancer
Acinar morphogenesis
RWPE-1
TGF-β
Matrix metalloprotease
Publication Status
Published