Li Yang, Liu Hengxin, Liang Yingzi, Peng Pai, Ma Xianjie, Zhang Xi
Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Biomed Pharmacother. 2017 Jul;91:174-180. doi: 10.1016/j.biopha.2017.03.044. Epub 2017 Apr 28.
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.
据报道，已对瘢痕疙瘩成纤维细胞中Dickkopf-3（DKK3）的下调情况进行了检测，但DKK3的生物学功能尚未得到研究。在本研究中，我们检测了DKK3在人瘢痕疙瘩组织中的表达，进一步评估了DKK3的生物学功能，并探讨了其在转化生长因子-β1（TGF-β1）诱导的瘢痕疙瘩成纤维细胞中的潜在分子机制。我们的结果表明，人瘢痕疙瘩组织中DKK3 mRNA表达下调。在转染了pcDNA3.1-DKK3的TGF-β1诱导的瘢痕疙瘩成纤维细胞中，DKK3过表达抑制了细胞增殖。此外，DKK3过表达显著上调了Bax和caspase-3的蛋白表达水平，但降低了Bcl-2的蛋白表达。此外，DKK3过表达显著抑制了I型胶原（Col-I）、III型胶原（Col-III）和α-平滑肌肌动蛋白（α-SMA）的蛋白和mRNA水平。而且，pcDNA3.1-DKK3显著抑制了TGF-β受体I（TGF-β RI）、TGF-β受体II（TGF-β RII）、Smad2（p-Smad2）和Smad3（p-Smad3）的磷酸化。TGF-β受体抑制剂LY2109761也抑制了TGF-β1诱导的瘢痕疙瘩成纤维细胞的细胞增殖、凋亡和胶原合成。综上所述，在TGF-β1诱导的瘢痕疙瘩成纤维细胞中，DKK3过表达可通过TGF-β1/Smad信号通路抑制细胞增殖、诱导细胞凋亡并抑制胶原合成。我们的研究结果表明，DKK3是瘢痕疙瘩治疗的一个新的且有前景的分子靶点。
