Systems analysis reveals a transcriptional reversal of the mesenchymal phenotype induced by SNAIL-inhibitor GN-25.
Systems analysis reveals a transcriptional reversal of the mesenchymal phenotype induced by SNAIL-inhibitor GN-25.
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DOI：
10.1186/1752-0509-7-85
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发表时间：
2013-09-03
影响因子：
--
通讯作者：
Mohammad RM
中科院分区：
文献类型：
--
作者：
Azmi AS;Bollig-Fischer A;Bao B;Park BJ;Lee SH;Yong-Song G;Dyson G;Reddy CK;Sarkar FH;Mohammad RM
HMLE（HMLE-SNAIL和Kras-HMLE，Kras-HMLE-SNAIL对）是研究逆转上皮-间充质转化（EMT）的SNAIL靶向药物作用的极好模型系统。我们早期开发了一种SNAIL-p53相互作用抑制剂（GN-25），其显示出抑制SNAIL功能。在这份报告中，使用系统生物学和通路网络分析，我们表明，GN-25可以引起EMT逆转，导致间充质上皮转化（MET）在公认的HMLE-SNAIL和Kras-HMLE-SNAIL模型。发现GN-25诱导的MET与生长抑制、球体形成能力抑制和诱导凋亡一致。使用来自GN-25处理的Kras-HMLE-SNAIL细胞的微阵列的mRNA表达的通路网络分析显示了EMT网络基因的协调的全局重组。在蛋白质水平上验证了表达特征（间充质标志物如TWIST 1和TWIST 2的下调与上皮标志物E-钙粘蛋白的上调同时发生），RNAi研究验证了药物作用的SNAIL依赖性机制。最重要的是，GN-25调节许多主要转录因子（TF），如抑制致癌TF Myc、TBX 2、NR 3C 1，并导致肿瘤抑制因子TF（如SMAD 7、DD 1 T3、CEBPA、HOXA 5、TFEB、IRF 1、IRF 7和XBP 1）表达增强，导致MET以及细胞死亡。我们的系统和网络研究提供了令人信服的临床前证据，支持GN-25逆转EMT的临床应用，从而降低癌细胞的侵袭性。
HMLEs (HMLE-SNAIL and Kras-HMLE, Kras-HMLE-SNAIL pairs) serve as excellent model system to interrogate the effect of SNAIL targeted agents that reverse epithelial-to-mesenchymal transition (EMT). We had earlier developed a SNAIL-p53 interaction inhibitor (GN-25) that was shown to suppress SNAIL function. In this report, using systems biology and pathway network analysis, we show that GN-25 could cause reversal of EMT leading to mesenchymal-to-epithelial transition (MET) in a well-recognized HMLE-SNAIL and Kras-HMLE-SNAIL models. GN-25 induced MET was found to be consistent with growth inhibition, suppression of spheroid forming capacity and induction of apoptosis. Pathway network analysis of mRNA expression using microarrays from GN-25 treated Kras-HMLE-SNAIL cells showed an orchestrated global re-organization of EMT network genes. The expression signatures were validated at the protein level (down-regulation of mesenchymal markers such as TWIST1 and TWIST2 that was concurrent with up-regulation of epithelial marker E-Cadherin), and RNAi studies validated SNAIL dependent mechanism of action of the drug. Most importantly, GN-25 modulated many major transcription factors (TFs) such as inhibition of oncogenic TFs Myc, TBX2, NR3C1 and led to enhancement in the expression of tumor suppressor TFs such as SMAD7, DD1T3, CEBPA, HOXA5, TFEB, IRF1, IRF7 and XBP1, resulting in MET as well as cell death. Our systems and network investigations provide convincing pre-clinical evidence in support of the clinical application of GN-25 for the reversal of EMT and thereby reducing cancer cell aggressiveness.
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影响因子：
29.4
作者：
Azmi AS;Aboukameel A;Bao B;Sarkar FH;Philip PA;Kauffman M;Shacham S;Mohammad RM
通讯作者：
Mohammad RM
影响因子：
8.4
作者：
Azmi, Asfar S.;Aboukameel, Amro;Banerjee, Sanjeev;Wang, Zhiwei;Mohammad, Momin;Wu, Jack;Wang, Shaomeng;Yang, Dajun;Philip, Philip A.;Sarkar, Fazlul H.;Mohammad, Ramzi M.
通讯作者：
Mohammad, Ramzi M.
DOI：
10.1186/bcr2938
发表时间：
2012-01-19
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dave B;Mittal V;Tan NM;Chang JC
通讯作者：
Chang JC
DOI：
10.1073/pnas.0906423106
发表时间：
2009-08-18
影响因子：
11.1
作者：
Harney, Allison S.;Lee, Jiyoun;Meade, Thomas J.
通讯作者：
Meade, Thomas J.
影响因子：
11.2
作者：
Casas E;Kim J;Bendesky A;Ohno-Machado L;Wolfe CJ;Yang J
通讯作者：
Yang J