DKK3 regulates cell proliferation, apoptosis and collagen synthesis in keloid fibroblasts via TGF-β1/Smad signaling pathway

It has been reported that Dickkopf-3 (DKK3) down-regulation was examined in keloid fibroblasts, but the biological functions of DKK3 have not yet been investigated. In this study, we examined the expression of DKK3 in human keloid tissues, further evaluated the biological function of DKK3 and explored its potential molecular mechanism in transforming growth factor-β1 (TGF-β1)-induced keloid fibroblasts. Our results showed that DKK3 mRNA expression in human keloid tissues is down-regulated. DKK3 overexpression inhibited cell proliferation in TGF-β1-induced keloid fibroblasts transfected with pcDNA3.1-DKK3. Furthermore, DKK3 overexpression remarkably upregulated the protein expression levels of Bax and caspase-3, but decreased the protein expression of Bcl-2. In addition, DKK3 overexpression dramatically inhibited the protein and mRNA levels of collagen I (Col-I), collagen III (Col-III) and α-smooth muscle actin (α-SMA). Moreover, the protein expression of TGF-β receptor I (TGF-β RI), TGF-β receptor II (TGF-β RII), the phosphorylation of Smad2 (p-Smad2) and Smad3 (p-Smad3) was dramatically inhibited by pcDNA3.1-DKK3. LY2109761, a TGF-β receptor inhibitor, also suppressed cell proliferation, apoptosis and collagen synthesis in TGF-β1-induced keloid fibroblasts. Taken together, DKK3 overexpression could inhibit cell proliferation, induced cell apoptosis, and suppressed collagen synthesis through TGF-β1/Smad signaling in TGF-β1-induced keloid fibroblasts. Our findings suggest that DKK3 is a novel and promising molecular target for keloid treatment.