Genome-wide screening reveals an EMT molecular network mediated by Sonic hedgehog-Gli1 signaling in pancreatic cancer cells.
Genome-wide screening reveals an EMT molecular network mediated by Sonic hedgehog-Gli1 signaling in pancreatic cancer cells.
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全基因组筛选揭示胰腺癌细胞中由 Sonic Hedgehog-Gli1 信号传导介导的 EMT 分子网络
DOI：
10.1371/journal.pone.0043119
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Guo C
中科院分区：
文献类型：
--
作者：
Xu X;Zhou Y;Xie C;Wei SM;Gan H;He S;Wang F;Xu L;Lu J;Dai W;He L;Chen P;Wang X;Guo C
目的sonic hedgehog基因（SHH）在胰腺癌（PC）上皮间质转化（epithelial mesenchymal transition， EMT）中的作用是已知的，但其机制尚不清楚。由于SHH主要通过Gli1促进肿瘤发展，我们试图通过识别胰腺癌细胞中的Gli1靶点来了解其机制。方法首先，我们在体外和体内研究了转染慢病毒Gli1干扰载体或SHH过表达载体的PC细胞的侵袭、迁移和EMT。接下来，我们利用cDNA芯片测定了PC细胞中Gli1的靶基因谱。最后，通过对这些靶点的功能分析，研究了PC细胞sh - gli1信号下游的主要调控网络。结果SHH/Gli1表达增加，E-cadherin表达减少。Gli1表达后24小时内，PC细胞的迁移量呈剂量依赖性增加（P<0.05）。激活sh - gli1信号后，裸鼠肝转移率和脾内微型转移率显著增加。利用基因芯片技术，我们在AsPC-1细胞中鉴定了Gli1表达上调的278个基因和下调的59个基因。数据表明sh - gli1信号通过介导包括TGFβ、Ras、Wnt、生长因子、PI3K/AKT、整合素、跨膜4超家族（TM4SF）和S100A4在内的复杂信号网络促进EMT。结论以SHH-Gli1信号通路与EMT之间的分子连接为靶点可提供有效的治疗方法。
Aims The role of sonic hedgehog (SHH) in epithelial mesenchymal transition (EMT) of pancreatic cancer (PC) is known, however, its mechanism is unclear. Because SHH promotes tumor development predominantly through Gli1, we sought to understand its mechanism by identifying Gli1 targets in pancreatic cancer cells. Methods First, we investigated invasion, migration, and EMT in PC cells transfected with lentiviral Gli1 interference vectors or SHH over-expression vectors in vitro and in vivo. Next, we determined the target gene profiles of Gli1 in PC cells using cDNA microarray assays. Finally, the primary regulatory networks downstream of SHH-Gli1 signaling in PC cells were studied through functional analyses of these targets. Results Our results indicate there is decreased E-cadherin expression upon increased expression of SHH/Gli1. Migration of PC cells increased significantly in a dose-dependent manner within 24 hours of Gli1 expression (P<0.05). The ratio of liver metastasis and intrasplenic miniature metastasis increased markedly upon activation of SHH-Gli1 signals in nude mice. Using cDNA microarray, we identified 278 upregulated and 59 downregulated genes upon Gli1 expression in AsPC-1 cells. The data indicate that SHH-Gli1 signals promote EMT by mediating a complex signaling network including TGFβ, Ras, Wnt, growth factors, PI3K/AKT, integrins, transmembrane 4 superfamily (TM4SF), and S100A4. Conclusion Our results suggest that targeting the molecular connections established between SHH-Gli1 signaling and EMT could provide effective therapies for PC.
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影响因子：
29.4
作者：
Mueller, Maria-Theresa;Hermann, Patrick C.;Heeschen, Christopher
通讯作者：
Heeschen, Christopher
影响因子：
11.5
作者：
Lee, Mei-Yi;Chou, Cheng-Yang;Shen, Meng-Ru
通讯作者：
Shen, Meng-Ru
影响因子：
2.8
作者：
Chen, Xiao-Feng;Zhang, Hui-Jun;Wang, He-Yong
通讯作者：
Wang, He-Yong
影响因子：
4.7
作者：
Soleti, Raffaella;Benameur, Tarek;Martinez, Maria Carmen
通讯作者：
Martinez, Maria Carmen
DOI：
10.1158/1541-7786.mcr-11-0399
发表时间：
2012-02
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Botta GP;Reginato MJ;Reichert M;Rustgi AK;Lelkes PI
通讯作者：
Lelkes PI