Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

Abstract

Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cell-conditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment.

Vitamin D Sufficiency Enhances Differentiation of Patient-Derived Prostate Epithelial Organoids

“…However, DKK3 is the most structurally divergent member of the Dickkopf family (Krupnik et al, 1999) and has varied effects on Wnt, ranging from no effect (Krupnik et al, 1999;Pinho Christof Niehrs, 2007;Romero et al, 2013) to promoting (Ferrari et al, 2019;Nakamura and Hackam, 2010;Yin et al, 2018) or inhibiting Wnt (Bhattacharyya et al, 2017;Leonard et al, 2017;Liu et al, 2019;Sharma Das et al, 2013). DKK3 also functions as both a positive and negative regulator of TGFβ signaling, depending on the model (Al Shareef et al, 2018;Busceti et al, 2017;Kardooni et al, 2018;Li et al, 2017;Pinho Christof Niehrs, 2007;Romero et al, 2013;Wang Z et al, 2015), but DKK3 did not impact TGFβ in this study (data not shown). Despite conflicting reports of DKK3's signaling targets, it has consistently been shown to restrain cell proliferation (Kawano et al, 2006;Leonard et al, 2017).…”

“…We observed that DKK3 was not expressed by the stem cells in organoids, similar to patient tissue (Henry et al, 2018), indicating that DKK3 acts downstream to regulate cell growth ( Figure 5E). Notably, DKK3 is also highly expressed in the stroma of the prostate, which indicates a multifaceted role for this protein that can be explored in the future using co-culture models (Al Shareef et al, 2018;Henry et al, 2018;Zenzmaier et al, 2013). The increase in organoid size induced by 1,25D may seem contradictory to the traditional anti-proliferative role of Vitamin D metabolites (Feldman et al, 2014;Murphy et al, 2017;Wagner et al, 2013).…”

The Influence of Pro-Inflammatory Factors on Sclerostin and Dickkopf-1 Production in Human Dental Pulp Cells Under Hypoxic Conditions

“…Also in the current study, measurement of SOST and DKK-1 remains a major challenge. Current literature reports that pro-inflammatory markers, including IL-1β, TNFα and TGFβ (Loots et al, 2012;Weng et al, 2012;Korkosz et al, 2014;Sebastian and Loots, 2017;Al Shareef et al, 2018), can increase Sost and Dkk-1 in bone and cartilage by transcriptional control. This finding could not be reproduced in our study with DPC.…”

“…In human DPC, the hypoxia mimetic agent L-mimosine (L-MIM) downregulated SOST and hypoxia downregulated DKK-1 mRNA production, but this effect could not be reproduced at protein levels, where SOST and DKK-1 were only produced marginally or not at all (Janjić et al, 2018a). Interleukin (IL)-1 (Weng et al, 2012;Ruscitti et al, 2015), tumor necrosis factor (TNF)α (Korkosz et al, 2014;Sebastian and Loots, 2017) and transforming growth factor (TGF)β (Loots et al, 2012;Al Shareef et al, 2018), markers of inflammation, are able to increase levels of Sost and Dkk-1.…”

Angioregulatory microRNAs in Colorectal Cancer

“…Exosome-mediated transfer of miR-92a from colon cancer cells to endothelial cells leads to angiogenesis induction through downregulation of Dickkopf-3 (DKK3) and claudin-11 [36]. Several studies have shown that DKK3 has a diverse function in tumor angiogenesis and oncogenesis [103][104][105][106]. Busceti et al have indicated an angio-promoting role of DKK3 via VEGF upregulation [107].…”