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.
Carcinogenesis. 2015 Oct 26 [Epub ahead of print]
Diana Romero, Zainab Al-Shareef, Irantzu Gorroño-Etxebarria, Stephanie Atkins, Frances Turrell, Jyoti Chhetri, Nora Bengoa-Vergniory, Christoph Zenzmaier, Peter Berger, Jonathan Waxman, Robert M Kypta
Department of Surgery and Cancer, Imperial College London, London, UK. , Department of Surgery and Cancer, Imperial College London, London, UK. , Cell Biology and Stem Cells Unit, CIC bioGUNE, Bilbao, Spain. , Department of Surgery and Cancer, Imperial College London, London, UK. , Department of Surgery and Cancer, Imperial College London, London, UK. , Department of Surgery and Cancer, Imperial College London, London, UK. , Cell Biology and Stem Cells Unit, CIC bioGUNE, Bilbao, Spain Present address Department of Physiology, Anatomy and Genetics, Oxford University, UK. , Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria Present address University of Applied Sciences Tyrol, Innsbruck, Austria. , Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria. , Department of Surgery and Cancer, Imperial College London, London, UK. , Department of Surgery and Cancer, Imperial College London, London, UK Cell Biology and Stem Cells Unit, CIC bioGUNE, Bilbao, Spain