同济大学用全基因组筛查技术揭胰腺癌特定分子网络
近日来自同济大学上海第十人民医院的研究人员发表了题为“Genome-Wide Screening Reveals an EMT Molecular Network Mediated by Sonic Hedgehog-Gli1 Signaling in Pancreatic Cancer Cells.”的研究论文，通过全基因组筛查揭示了胰腺癌细胞中由Sonic Hedgehog-Gli1信号介导的EMT分子网络。相关成果发布在《PLos ONE》杂志上。
领导这一研究是上海市第十人民医院消化科主任郭传勇教授，其主要研究方向为中西医结合防治慢性肝病机理研究以及消化道肿瘤的早期诊断和综合防治研究等，发表论文100余篇。
全基因组筛查技术揭胰腺癌特定分子网络
Hedgehog信号通路在脊椎动物和无脊椎动物发育过程中发挥多种重要作用。近年来的研究发现脊椎动物Hedgehog信号通路成员之一Sonic hedgehog (SHH)在胰腺癌中过度表达,并被认为在胰腺癌上皮间质转化（EMT）中起重要作用，然而目前对于其机制仍不是很清楚。SHH主要通过Gli1促进了肿瘤形成，研究人员试图通过鉴别在胰腺癌细胞中的Gli1靶标来了解其机制。
首先，研究人员在体内外调查了转染慢病毒Gli1干扰载体或SHH过表达载体的胰腺癌细胞的侵袭、迁移和EMT。随后，他们利用cDNA微阵列分析确定了在胰腺癌细胞中Gli1靶向基因图谱。最后通过对这些靶标进行功能分析研究了胰腺癌中SHH-Gli1信号下游主要调控网络。
研究结果表明当SHH/Gli1表达增高时E-cadherin表达下降。在Gli1表达的24小时内，胰腺癌细胞的迁移以一种剂量依赖的方式显著增高。在裸鼠中当激活SHH-Gli1信号时，肝转移和脾内小规模转移的比例显著增加。利用cDNA微阵列，研究人员在AsPC-1细胞中鉴别出了Gli1表达时278种上调和59种下调的基因。这些数据表明SHH-Gli1信号通过介导包括TGFβ、Ras、Wnt、生长因子、PI3K/AKT、integrins、四跨膜蛋白超家族(TM4SF)和S100A4的一个复杂信号网络促进了上皮间质转化。
新研究结果表明靶向SHH-Gli1信号和EMT之间建立的分子联系有可能为胰腺癌提供新的有效的治疗途径。
Genome-Wide Screening Reveals an EMT Molecular Network Mediated by Sonic Hedgehog-Gli1 Signaling in Pancreatic Cancer Cells
Xuanfu Xu, Yingqun Zhou, Chuangao Xie, Shu-mei Wei, Huizhong Gan, Shengli He, Fan Wang, Ling Xu, Jie Lu, Weiqi Dai, Lei He, Ping Chen, Xingpeng Wang, Chuanyong Guo
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.
文献链接： Genome-Wide Screening Reveals an EMT Molecular Network Mediated by Sonic Hedgehog-Gli1 Signaling in Pancreatic Cancer Cells
