The human DEK oncogene stimulates β-catenin signaling, invasion and mammosphere formation in breast cancer.
The human DEK oncogene stimulates β-catenin signaling, invasion and mammosphere formation in breast cancer.
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DOI：
10.1038/onc.2011.2
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发表时间：
2011-06-16
期刊：
影响因子：
8
通讯作者：
Wells, S. I.
中科院分区：
文献类型：
--
作者：
Vinnedge, L. M. Privette;McClaine, R.;Wagh, P. K.;Wikenheiser-Brokamp, K. A.;Waltz, S. E.;Wells, S. I.
乳腺癌是美国女性癌症相关死亡的主要原因；因此，识别新的乳腺癌相关分子以发现新的标志物和药物靶点仍然至关重要。人类DEK基因编码染色质结合蛋白和DNA拓扑调节因子，在许多类型的癌症中上调。基于mRNA表达的研究，DEK已被认为是乳腺癌中的癌基因，但其在乳腺癌生长和发展中的功能意义尚未得到直接测试。我们证明，与正常组织相比，DEK在乳腺癌细胞中高度表达，并且在功能上对细胞生长、侵袭和乳房大气层的形成具有重要作用。在非致癌的MCF10A细胞中，DEK的过度表达导致生长和运动能力的增加，同时伴随着E-钙粘蛋白的下调。相反，在MCF7和MDA-MB-468乳腺癌细胞中，DEK基因敲除导致E-钙粘蛋白上调，导致生长和运动能力下降。在原位异种移植中使用精通DEK和缺乏DEK的乳腺癌细胞提供了进一步的体内证据，证明DEK有助于肿瘤生长。β-连环蛋白信号通路的激活对正常和肿瘤干细胞的特性、生长和转移具有重要意义。我们发现DEK的表达促进了β-连环蛋白的核转位和活性，而DEK基因敲除抑制了DNA-连环蛋白的核转移和活性。重要的是，结构性活性β-连环蛋白的表达挽救了乳腺癌DEK基因敲除细胞的侵袭缺陷。总之，我们的数据表明，DEK的表达刺激了乳腺癌细胞的生长、干细胞特性和运动能力，并且DEK依赖的细胞侵袭至少部分通过β-连环蛋白的激活而发生。
Breast cancer is a major cause of cancer-related deaths in American women; therefore, the identification of novel breast-cancer related molecules for the discovery of new markers and drug targets remains essential. The human DEK gene, which encodes a chromatin-binding protein and DNA topology regulator, is up-regulated in many types of cancer. DEK has been implicated as an oncogene in breast cancer based on mRNA expression studies, but its functional significance in breast cancer growth and progression has not yet been tested directly. We demonstrate that DEK is highly expressed in breast cancer cells compared to normal tissue, and functionally important for cellular growth, invasion and mammosphere formation. DEK over-expression in non-tumorigenic MCF10A cells resulted in increased growth and motility with a concomitant down-regulation of E-cadherin. Conversely, DEK knockdown in MCF7 and MDA-MB-468 breast cancer cells resulted in decreased growth and motility with up-regulation of E-cadherin. The use of DEK-proficient and -deficient breast cancer cells in orthotopic xenografts provided further in vivo evidence that DEK contributes to tumor growth. Activation of the β-catenin signaling pathway is important for normal and cancer stem cell character, growth and metastasis. We show that DEK expression stimulated and DEK knockdown repressed β-catenin nuclear translocation and activity. Importantly, the expression of constitutively active β-catenin rescued breast cancer invasion defects of DEK knockdown cells. Together, our data indicate that DEK expression stimulates the growth, stem cell character, and motility of breast cancer cells, and that DEK-dependent cellular invasion occurs at least in part via β-catenin activation.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
DOI：
10.1083/jcb.127.3.789
发表时间：
1994-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Andreassen PR;Margolis RL
通讯作者：
Margolis RL
DOI：
10.1385/scr:1:3:207
发表时间：
2005-01-01
期刊：
STEM CELL REVIEWS
影响因子：
--
作者：
Dontu, Gabriela;Liu, Suling;Wicha, Max S.
通讯作者：
Wicha, Max S.
影响因子：
14.9
作者：
Campillos, M;García, MA;Vázquez, J
通讯作者：
Vázquez, J
影响因子：
11.4
作者：
Le Hir, H;Gatfield, D;Moore, MJ
通讯作者：
Moore, MJ