Dickkopf-related protein 3 promotes cell adhesion and invasion during progression of lung adenocarcinoma.

Dickkopf-related protein 3 (DKK3) is one of the DKK family (DKK1-4), an evolutionally conserved group of secreted glycoproteins characterized by two distinct cysteine-rich domains. DKK3 is considered to be a tumor suppressor gene. However, it has been shown that 30-50% of various cancers are DKK3-positive, suggesting that DKK3 may have an additional function other than tumor suppression. In this study, we focused on lung adenocarcinoma, which is the major histological type of lung cancer. We analyzed the relationship between DKK3 expression and clinicopathological features by immunohistochemistry, using 200 lung adenocarcinoma specimens. We found that 40.5% and 59.5% of cases were DKK3-positive and -negative, respectively, and that positive cases had a greater tendency for progression than negative cases (P < 0.05). Furthermore, in vitro analyses demonstrated that DKK3 suppression affected cell adhesion in three DKK3-expressing lung adenocarcinoma cell lines and that DKK3-knockdown cells were less invasive in comparison to control cells. These results suggest that DKK3 plays a role in the progression of lung adenocarcinoma by promoting cell adhesion and invasion. DKK3 might be a new extracellular cancer therapeutic target, and it seems important to clarify molecular mechanisms underlying the DKK3 functions depending on cell context.