Epigenetic silencing of the WNT antagonist Dickkopf 3 disrupts normal Wnt/β-catenin signalling and apoptosis regulation in breast cancer cells.
Epigenetic silencing of the WNT antagonist Dickkopf 3 disrupts normal Wnt/β-catenin signalling and apoptosis regulation in breast cancer cells.
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DOI：
10.1111/jcmm.12099
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发表时间：
2013-10
影响因子：
5.3
通讯作者：
Tao Q
中科院分区：
文献类型：
--
作者：
Xiang T;Li L;Yin X;Zhong L;Peng W;Qiu Z;Ren G;Tao Q
dickkopf相关蛋白3 （DKK3）是Wnt配体活性的拮抗剂。DKK3在各种类型的癌症中表达降低，但其在乳腺肿瘤发生中的功能和相关分子机制尚不清楚。我们检测了10种乳腺癌细胞系、96种原发性乳腺肿瘤、43对手术边缘组织和16种正常乳腺组织中DKK3的表达和启动子甲基化。与人类正常乳腺上皮细胞和组织相比，DKK3在乳腺细胞系中通过启动子甲基化经常沉默（5/10）。在78%的乳腺肿瘤样本中检测到DKK3甲基化，而在正常乳腺和手术边缘组织中很少甲基化，这表明DKK3在乳腺癌中存在肿瘤特异性甲基化。DKK3异位表达通过诱导乳腺肿瘤细胞G0/G1周期阻滞和凋亡抑制细胞集落形成。DKK3还通过逆转上皮-间质转化（epithelial-mesenchymal transition， EMT）和下调干细胞标记物来诱导细胞形态改变，抑制乳腺肿瘤细胞迁移。DKK3通过介导β-catenin从细胞核向细胞质和细胞膜的易位，抑制典型Wnt/β-catenin信号传导，同时降低活性β-catenin，进一步激活非典型JNK信号传导。因此，我们的研究结果表明，DKK3可能通过诱导细胞凋亡和调节乳腺肿瘤发生过程中的Wnt信号传导而发挥肿瘤抑制作用。
Dickkopf-related protein 3 (DKK3) is an antagonist of Wnt ligand activity. Reduced DKK3 expression has been reported in various types of cancers, but its functions and related molecular mechanisms in breast tumorigenesis remain unclear. We examined the expression and promoter methylation of DKK3 in 10 breast cancer cell lines, 96 primary breast tumours, 43 paired surgical margin tissues and 16 normal breast tissues. DKK3 was frequently silenced in breast cell lines (5/10) by promoter methylation, compared with human normal mammary epithelial cells and tissues. DKK3 methylation was detected in 78% of breast tumour samples, whereas only rarely methylated in normal breast and surgical margin tissues, suggesting tumour-specific methylation of DKK3 in breast cancer. Ectopic expression of DKK3 suppressed cell colony formation through inducing G0/G1 cell cycle arrest and apoptosis of breast tumour cells. DKK3 also induced changes of cell morphology, and inhibited breast tumour cell migration through reversing epithelial-mesenchymal transition (EMT) and down-regulating stem cell markers. DKK3 inhibited canonical Wnt/β-catenin signalling through mediating β-catenin translocation from nucleus to cytoplasm and membrane, along with reduced active-β-catenin, further activating non-canonical JNK signalling. Thus, our findings demonstrate that DKK3 could function as a tumour suppressor through inducing apoptosis and regulating Wnt signalling during breast tumorigenesis.
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DOI：
10.1186/bcr3375
发表时间：
2013-01-15
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Kloten V;Becker B;Winner K;Schrauder MG;Fasching PA;Anzeneder T;Veeck J;Hartmann A;Knüchel R;Dahl E
通讯作者：
Dahl E
DOI：
10.3109/08977191003738832
发表时间：
2010-08
期刊：
Growth factors (Chur, Switzerland)
影响因子：
--
作者：
Nakamura RE;Hackam AS
通讯作者：
Hackam AS
影响因子：
4.3
作者：
Ding, Zhen;Qian, Ye-Ben;Xiong, Qi-Ru
通讯作者：
Xiong, Qi-Ru
影响因子：
6.4
作者：
Lee, Eun-Ju;Jo, Minwha;Lee, Je-Ho
通讯作者：
Lee, Je-Ho
影响因子：
4.7
作者：
Ai, Lingbao;Tao, Qian;Robertson, Keith D.
通讯作者：
Robertson, Keith D.