Roles of <scp>DKK3</scp> in cellular adhesion, motility, and invasion through extracellular interaction with <scp>TGFBI</scp>

Dickkopf-related protein (DKK) 3, a member of the DKK family, is a secreted glycoprotein that acts as a modulator of WNT signaling in organogenesis and carcinogenesis. Recent studies have demonstrated that DKK3 has a variety of functions, suggesting that it plays roles not only in tumorigenesis, but also tumor neovascularization, prostatic acinus formation, cardiac vascular remodeling, renal and cardiac fibrosis, and immunological activity. The function of DKK3 is therefore of great interest, but details of the receptors and mechanisms involved have remained unclear. Here we focused on the extracellular function of DKK3 as a secreted protein, and identified Transforming Growth Factor Beta Induced protein ig-h3 (TGFBI) as a secreted protein interacting with DKK3. To investigate the function of these secreted proteins, we employed an in vitro cell model involving human hepatocellular carcinoma cells, human embryonic kidney cells, or non-neoplastic hepatocyte cells. We showed that DKK3 functions as an extracellular matrix-like molecule supporting adhesion, motility, and invasion, and that its interaction with TGFBI inhibits the functions of secreted DKK3 in cells expressing both proteins. These results suggest that this extracellular interaction between DKK3 and TGFBI modulates cell adhesion and motility through focal adhesion kinase signaling, and that this might serve as a potential therapeutic target in the context of cancer invasion and metastasis.