Department of Gastroenterology, Second Affiliated Hospital, School of Medicine Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China.
BMC Cancer. 2012 Jul 16;12:290. doi: 10.1186/1471-2407-12-290.
ZIC1, 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.
The role of ZIC1 on cell proliferation and migration was examined. The regulation of sonic hedgehog (Shh), phosphoinositide 3-kinase (PI(3)K) and mitogen-activated protein kinase (MAPK) signaling pathways after ectopic expression of ZIC1 in gastric cancer cells were evaluated.
Overexpression 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 (p21(Waf1/Cip1), p27(Kip1) and 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 p21(Waf1/Cip1) and 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.
Overexpression of ZIC1 results in inactivation of Shh, PI(3)K 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.
锌指蛋白 1（ZIC1）是一种具有锌指结构域的重要转录因子，与神经发育过程有关。我们之前的研究表明，ZIC1 可能作为胃肠道癌症的肿瘤抑制因子发挥作用。然而，ZIC1 参与肿瘤进展的分子机制尚不清楚。
研究了 ZIC1 对细胞增殖和迁移的作用。评估了胃癌细胞中过表达 ZIC1 后 sonic hedgehog（Shh）、磷酸肌醇 3-激酶（PI(3)K）和丝裂原活化蛋白激酶（MAPK）信号通路的调节。
ZIC1 的过表达有助于抑制胃癌细胞的增殖、迁移和细胞周期分布。ZIC1 通过调节细胞周期蛋白依赖性激酶（p21(Waf1/Cip1)、p27(Kip1) 和细胞周期蛋白 D1）主要介导 G1/S 检查点的调节。此外，ZIC1 可以使磷酸化 Akt 和 Erk1/2 的水平失活，并转录调控 sonic hedgehog（Shh）信号，从而调节 p21(Waf1/Cip1) 和细胞周期蛋白 D1 的表达。最后，我们通过 cDNA 微阵列分析系统地鉴定了 ZIC1 的下游靶标，发现在胃癌细胞中转染 ZIC1 后，有 132 个基因下调，66 个基因上调。这些候选基因在细胞增殖、细胞周期和细胞迁移中发挥关键作用。
ZIC1 的过表达导致 Shh、PI(3)K 和 MAPK 信号通路失活，以及多个下游靶标的调节，这些靶标对于胃癌的发生和发展至关重要。ZIC1 可能成为胃癌的潜在治疗靶点。
