Dickkopf-related protein 2 induces G0/G1 arrest and apoptosis through suppressing Wnt/β-catenin signaling and is frequently methylated in breast cancer.
Dickkopf-related protein 2 induces G0/G1 arrest and apoptosis through suppressing Wnt/β-catenin signaling and is frequently methylated in breast cancer.
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Dickkopf 相关蛋白 2 通过抑制 Wnt/β-连环蛋白信号传导诱导 G0/G1 停滞和细胞凋亡，并且在乳腺癌中经常被甲基化
DOI：
10.18632/oncotarget.17055
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发表时间：
2017-06-13
期刊：
影响因子：
--
通讯作者：
Xiang T
中科院分区：
文献类型：
--
作者：
Mu J;Hui T;Shao B;Li L;Du Z;Lu L;Ye L;Li S;Li Q;Xiao Q;Qiu Z;Zhang Y;Fan J;Ren G;Tao Q;Xiang T
Dickkopf-Related Protein 2(DKK2)是Wnt/β-catenin信号通路的拮抗剂之一，据报道其在多种癌症中表达下调。然而，DKK2如何在乳腺肿瘤发生中起作用仍不清楚。我们检测了它在10个乳腺肿瘤细胞系、98个原发肿瘤和21个正常乳腺组织中的表达和启动子甲基化。与正常组织相比，DKK2在乳腺细胞系中经常被沉默(7/8)。DKK2启动子甲基化在77.8%的细胞株和86.7%的乳腺肿瘤中检测到，而在正常乳腺组织中很少检测到(19%)，提示乳腺癌中常见的DKK2甲基化。DKK2的异位表达改变了乳腺肿瘤细胞的形态，通过诱导G0/G1期细胞停滞和凋亡来抑制细胞增殖和集落形成，通过逆转上皮-间充质转化(EMT)和下调干细胞标志来抑制肿瘤细胞的迁移。此外，DKK2在MCF7细胞中的恢复表达破坏了人脐静脉内皮细胞在Matrigel®上的微管形成。在体内，稳定表达DKK2后，裸鼠体内的MDA-MB-231细胞生长明显下降。DKK2通过抑制β-连环蛋白的活性，抑制β-连环蛋白的活性，从而抑制规范的Wnt/β-连环蛋白信号转导。因此，我们的研究结果表明，DKK2在乳腺肿瘤发生过程中通过调节Wnt信号抑制细胞增殖和诱导细胞凋亡，从而发挥肿瘤抑制作用。
Dickkopf-related protein 2 (DKK2) is one of the antagonists of Wnt/β-catenin signaling, with its downregulation reported in multiple cancers. However, how DKK2 contributes to breast tumorigenesis remains unclear. We examined its expression and promoter methylation in 10 breast tumor cell lines, 98 primary tumors, and 21 normal breast tissues. Compared with normal tissues, DKK2 was frequently silenced in breast cell lines (7/8). DKK2 promoter methylation was detected in 77.8% of cell lines and 86.7% of breast tumors; while rarely detected in normal breast tissues (19%), indicating common DKK2 methylation in breast cancer. Ectopic expression of DKK2 changed breast tumor cell morphology, inhibited cell proliferation and colony formation by inducing G0/G1 cell cycle arrest and apoptosis, and suppressed tumor cell migration by reversing epithelial-mesenchymal transition (EMT) and downregulating stem cell markers. Moreover, restored expression of DKK2 in MCF7 cells disrupted the microtube formation of human umbilical vein endothelial cells on Matrigel®. In vivo, the growth of MDA-MB-231 cells in nude mice was markedly decreased after stable expression of DKK2. DKK2 suppressed canonical Wnt/β-catenin signaling by inhibiting β-catenin activity with decreased active β-catenin protein. Thus, our findings demonstrate that DKK2 functions as a tumor suppressor through inhibiting cell proliferation and inducing apoptosis via regulating Wnt signaling during breast tumorigenesis.
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影响因子：
11.2
作者：
Hauer, Kristina;Calzada-Wack, Julia;Richter, Guenther H. S.
通讯作者：
Richter, Guenther H. S.
影响因子：
4.7
作者：
Ai, Lingbao;Tao, Qian;Robertson, Keith D.
通讯作者：
Robertson, Keith D.
影响因子：
3.6
作者：
Li, Jisheng;Ying, Jianming;Tao, Qian
通讯作者：
Tao, Qian
影响因子：
6
作者：
Muley, Ajit;Majumder, Syamantak;Chatterjee, Suvro
通讯作者：
Chatterjee, Suvro
影响因子：
4.7
作者：
Veeck, Juergen;Geisler, Cordelia;Dahl, Edgar
通讯作者：
Dahl, Edgar