The endogenous cell-fate factor dachshund restrains prostate epithelial cell migration via repression of cytokine secretion via a cxcl signaling module.
The endogenous cell-fate factor dachshund restrains prostate epithelial cell migration via repression of cytokine secretion via a cxcl signaling module.
复制标题
DOI：
10.1158/0008-5472.can-14-0611
复制
发表时间：
2015-05-15
期刊：
影响因子：
11.2
通讯作者：
Pestell RG
中科院分区：
文献类型：
--
作者：
Chen K;Wu K;Jiao X;Wang L;Ju X;Wang M;Di Sante G;Xu S;Wang Q;Li K;Sun X;Xu C;Li Z;Casimiro MC;Ertel A;Addya S;McCue PA;Lisanti MP;Wang C;Davis RJ;Mardon G;Pestell RG
前列腺癌（PCa）是男性癌症死亡的第二大形式。在PCa患者的子集中，趋化因子信号传导IL-8和IL-6增加与雄激素治疗抵抗性前列腺癌（CRPC）相关。IL-8和IL-6由前列腺上皮细胞产生并促进PCa细胞的侵袭，但抑制前列腺上皮细胞分泌细胞因子的机制知之甚少。在此，细胞命运决定因子DACH 1抑制小鼠雄激素治疗抵抗性前列腺癌（CRPC）肿瘤生长。使用Dach 1fl/fl/Probasin-Cre双转基因小鼠，我们显示IL-8和IL-6分泌被内源性Dach 1改变约1000倍。内源性Dach 1被证明是前列腺上皮细胞生长的关键内源性抑制因子，并通过CXCL信号传导抑制迁移。DACH 1通过与CXCL基因（IL-8、IL-6）的启动子调控区结合，抑制CXCL基因的表达、转录和分泌。因此，DACH 1是体内良性和恶性前列腺上皮细胞生长、迁移和细胞因子丰度的新定义的决定因素。
Prostate cancer (PCa) is the second leading form of cancer death in men. In a subset of PCa patients increased chemokine signaling IL-8 and IL-6 correlates with androgen therapy-resistant prostate cancer (CRPC). IL-8 and IL-6 are produced by prostate epithelial cells and promote PCa cell invasion, however the mechanisms restraining prostate epithelial cell cytokine secretion are poorly understood. Herein the cell-fate determinant factor DACH1 inhibited androgen therapy-resistant prostate cancer (CRPC) tumor growth in mice. Using Dach1fl/fl/Probasin-Cre bi-transgenic mice, we show IL-8 and IL-6 secretion was altered ~1000 fold by endogenous Dach1. Endogenous Dach1 is shown to serve as a key endogenous restraint to prostate epithelial cell growth and restrains migration via CXCL signaling. DACH1 inhibited expression, transcription and secretion of the CXCL genes (IL-8, IL-6) by binding to their promoter regulatory regions in chromatin. DACH1 is thus a newly defined determinant of benign and malignant prostate epithelium cellular growth, migration and cytokine abundance in vivo.