ZIC1 modulates cell-cycle distributions and cell migration through regulation of sonic hedgehog, PI3K and MAPK signaling pathways in gastric cancer
ZIC1 modulates cell-cycle distributions and cell migration through regulation of sonic hedgehog, PI3K and MAPK signaling pathways in gastric cancer
复制标题
ZIC1 通过调节胃癌中的 sonic hedgehog、PI3K 和 MAPK 信号通路来调节细胞周期分布和细胞迁移
DOI：
10.1186/1471-2407-12-290
复制
发表时间：
2012-07-16
期刊：
影响因子：
3.8
通讯作者：
Wang, Liangjing
中科院分区：
文献类型：
--
作者：
Zhong, Jing;Chen, Shujie;Wang, Liangjing
zic1是具有锌指结构域的重要转录因子，参与神经发育过程。我们之前表明ZIC1可能在胃肠道癌症中起肿瘤抑制作用。然而，ZIC1参与肿瘤进展的分子机制尚不清楚。方法观察ZIC1对细胞增殖和迁移的影响。研究胃癌细胞异位表达ZIC1后，超音hedgehog基因（Shh）、磷酸肌肽3激酶（PI3K）和丝裂原活化蛋白激酶（MAPK）信号通路的调控。结果ZIC1过表达对胃癌细胞增殖迁移和细胞周期分布有抑制作用。ZIC1对G1/S检查点的调节主要通过调节细胞周期蛋白依赖性激酶（p21Waf1/Cip1、p27kip1和cyclin D1）介导。此外，ZIC1可使磷酸化Akt和Erk1/2水平失活，通过转录调控sonic hedgehog （Shh）信号通路，从而调控p21Waf1/ cip1和cyclin D1的表达。最后，我们通过cDNA芯片分析系统鉴定了ZIC1的下游靶点，发现转染ZIC1后，胃癌细胞中有132个基因下调，66个基因上调。这些候选基因在细胞增殖、细胞周期和细胞运动中起着关键作用。结论ZIC1过表达导致Shh、PI3K和MAPK信号通路失活，并调控多种下游靶点，这些靶点在胃癌的发生发展中至关重要。ZIC1是胃癌的潜在治疗靶点。
BackgroundZIC1, a vital transcription factor with zinc finger domains, has been implicated in the process of neural development. We previously showed that ZIC1 may function as a tumour suppressor in gastrointestinal cancers. However, the molecular mechanism underlying ZIC1 participation in tumour progression remains unknown.MethodsThe role of ZIC1 on cell proliferation and migration was examined. The regulation of sonic hedgehog (Shh), phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways after ectopic expression of ZIC1 in gastric cancer cells were evaluated.ResultsOverexpression of ZIC1 contributes to the inhibition of cell proliferation migration and cell-cycle distribution in gastric cancer. The modulation of G1/S checkpoint by ZIC1 is mainly mediated through the regulation of cyclin-dependent kinases (p21Waf1/Cip1, p27Kip1and cyclin D1). In addition, ZIC1 can inactivate the level of phospholated Akt and Erk1/2, and transcriptionally regulate sonic hedgehog (Shh) signaling, thus leading to regulate the expression of p21Waf1/Cip1and cyclin D1. Finally, we have systemically identified ZIC1 downstream targets by cDNA microarray analysis and revealed that 132 genes are down-regulated and 66 genes are up-regulated after transfection with ZIC1 in gastric cancer cells. These candidate genes play critical roles in cell proliferation, cell cycle and cell motility.ConclusionsOverexpression of ZIC1 results in inactivation of Shh, PI3K and MAPK signaling pathways, as well as regulation of multiple downstream targets which are essential for the development and progression of gastric cancer. ZIC1 serves as a potential therapeutic target for gastric cancer.