Regulation of prostate cell growth and morphogenesis by Dickkopf-3
Regulation of prostate cell growth and morphogenesis by Dickkopf-3
复制标题
DOI：
10.1038/sj.onc.1209661
复制
发表时间：
2006-10-19
期刊：
影响因子：
8
通讯作者：
Kypta, R. M.
中科院分区：
文献类型：
--
作者：
Kawano, Y.;Kitaoka, M.;Kypta, R. M.
Wnt信号在癌症的发展中起着关键作用。最近的研究表明，Wnt信号传导受分泌型Wnt拮抗剂如分泌型卷曲相关蛋白（sFRPs）和Dick-kopfs（Dkks）的负调控。我们比较了正常前列腺和前列腺癌细胞中Dkk家族的表达水平，发现癌细胞中Dkk-3表达减少。Dkk-3的异位表达抑制LNCaP和PC 3前列腺癌细胞系中的集落形成，并且Dkk-3的诱导表达降低LNCaP细胞增殖。此外，在未转化的RWPE-1前列腺上皮细胞中，小干扰RNA介导的Dkk-3下调增强了细胞周期进程。免疫组化分析显示，Dkk-3在正常前列腺泡的一个子集中表达，并且Dkk-3在前列腺肿瘤中表达减少，特别是那些具有高Gleason分级的前列腺肿瘤，这表明Dkk-3在有丝分裂后分化中的作用。与此一致，在三维细胞培养模型中，Dkk-3的耗竭破坏了RWPE-1细胞的腺泡形态发生。我们的结果与Dkk-3表达的缺失导致腺体结构受损和不受控制的前列腺上皮细胞（PrEC）增殖一致，
Wnt signalling plays a critical role in the development of cancer. Recent studies indicate that Wnt signalling is negatively regulated by secreted Wnt antagonists such as secreted frizzled related proteins (sFRPs) and Dick-kopfs (Dkks). We compared Dkk family expression levels in normal prostate and prostate cancer cells and found a reduction in Dkk-3 expression in cancer cells. Ectopic expression of Dkk-3 inhibited colony formation in LNCaP and PC3 prostate cancer cell lines and inducible expression of Dkk-3 reduced LNCaP cell proliferation. Moreover, small interfering RNA-mediated downregulation of Dkk-3 enhanced cell cycle progression in untransformed RWPE-1 prostate epithelial cells. Immunohistochemical analysis revealed that Dkk-3 is expressed in a subset of normal prostate gland acini and that Dkk-3 expression is reduced in prostate tumours, particularly those with a high Gleason grade, suggesting a role for Dkk-3 in postmitotic differentiation. Consistent with this, depletion of Dkk-3 disrupted acinar morphogenesis of RWPE-1 cells in a three-dimensional cell culture model. Our results are consistent with the loss of Dkk-3 expression resulting in impairment of glandular structure and uncontrolled prostate epithelial cell ( PrEC) proliferation,