DEAD-box protein p68 is regulated by β-catenin/transcription factor 4 to maintain a positive feedback loop in control of breast cancer progression.
DEAD-box protein p68 is regulated by β-catenin/transcription factor 4 to maintain a positive feedback loop in control of breast cancer progression.
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DOI：
10.1186/s13058-014-0496-5
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发表时间：
2014-12-12
期刊：
影响因子：
--
通讯作者：
Ghosh MK
中科院分区：
文献类型：
--
作者：
Guturi KK;Sarkar M;Bhowmik A;Das N;Ghosh MK
临床研究和细胞系研究表明，β-catenin的核积累对癌症的发展很重要，并且在大多数乳腺癌中发现它与p68 （DDX5）免疫反应性重叠。本研究旨在探讨β-catenin/转录因子4 （TCF4）信号在乳腺癌中对p68基因表达的调控。采用福尔马林固定石蜡包埋切片，对正常乳腺和乳腺癌标本进行免疫组织化学分析。免疫印迹法和定量RT-PCR法分别检测蛋白和mRNA的表达。荧光素酶法检测p68启动子活性。利用染色质免疫沉淀法评估了p68启动子上几个因子的占用情况。最后，采用同基因小鼠乳腺癌模型来评估其生理意义。我们证明β-catenin可以直接诱导p68启动子的转录或间接通过调节c-Myc在人和小鼠乳腺癌细胞中。此外，通过染色质免疫沉淀实验，我们发现β-catenin和TCF4都占据内源性p68启动子，并通过Wnt信号进一步增强。此外，我们还建立了p68对TCF4表达的正反馈调控。据我们所知，这是第一篇关于β-catenin/ tcf4介导的p68基因调控的报道，该基因调控在乳腺癌细胞系的体外和动物乳腺肿瘤模型的体内上皮向间质转化中起着重要作用。我们的研究结果表明，Wnt/β-catenin信号通过p68上调在乳腺癌进展中起重要作用。本文的在线版本（doi:10.1186/s13058-014-0496-5）包含补充材料，可供授权用户使用。
Nuclear accumulation of β-catenin is important for cancer development and it is found to overlap with p68 (DDX5) immunoreactivity in most breast cancers, as indicated by both clinical investigations and studies in cell lines. In this study, we aim to investigate the regulation of p68 gene expression through β-catenin/transcription factor 4 (TCF4) signaling in breast cancer. Formalin-fixed paraffin-embedded sections derived from normal human breast and breast cancer samples were used for immunohistochemical analysis. Protein and mRNA expressions were determined by immunoblotting and quantitative RT-PCR respectively. Promoter activity of p68 was checked using luciferase assay. Occupancy of several factors on the p68 promoter was evaluated using chromatin immunoprecipitation. Finally, a syngeneic mouse model of breast cancer was used to assess physiological significance. We demonstrated that β-catenin can directly induce transcription of p68 promoter or indirectly through regulation of c-Myc in both human and mouse breast cancer cells. Moreover, by chromatin immunoprecipitation assay, we have found that both β-catenin and TCF4 occupy the endogenous p68 promoter, which is further enhanced by Wnt signaling. Furthermore, we have also established a positive feedback regulation for the expression of TCF4 by p68. To the best of our knowledge, this is the first report on β-catenin/TCF4-mediated p68 gene regulation, which plays an important role in epithelial to mesenchymal transition, as shown in vitro in breast cancer cell lines and in vivo in an animal breast tumour model. Our findings indicate that Wnt/β-catenin signaling plays an important role in breast cancer progression through p68 upregulation. The online version of this article (doi:10.1186/s13058-014-0496-5) contains supplementary material, which is available to authorized users.
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影响因子：
14.9
作者：
Fuller-Pace FV
通讯作者：
Fuller-Pace FV
影响因子：
3.7
作者：
Bhowmik A;Das N;Pal U;Mandal M;Bhattacharya S;Sarkar M;Jaisankar P;Maiti NC;Ghosh MK
通讯作者：
Ghosh MK
DOI：
10.1023/b:jomg.0000037157.94207.33
发表时间：
2004-04-01
影响因子：
2.5
作者：
Brennan, KR;Brown, AMC
通讯作者：
Brown, AMC
影响因子：
8.4
作者：
Jönsson, M;Borg, Å;Andersson, T
通讯作者：
Andersson, T
DOI：
10.1073/pnas.060025397
发表时间：
2000-04-11
影响因子：
11.1
作者：
Lin, SY;Xia, WY;Hung, MC
通讯作者：
Hung, MC