Email updates

Keep up to date with the latest news and content from BMC Cancer and BioMed Central.

Open Access Research article

ZIC1 modulates cell-cycle distributions and cell migration through regulation of sonic hedgehog, PI3K and MAPK signaling pathways in gastric cancer

Jing Zhong1, Shujie Chen2, Meng Xue2, Qin Du1, Jianting Cai1, Hongchuan Jin3, Jianmin Si2 and Liangjing Wang1*

Author affiliations

1 Department of Gastroenterology, Second Affiliated Hospital, School of Medicine Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, China

2 Laboratory of Digestive Disease, Sir Run run Shaw Clinical Medicine Institution of Zhejiang University, 3 Qingchun Road, Hangzhou, 310053, China

3 Key Laboratory of Biotherapy of Zhejiang Province, Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University, 3 Qingchun Road, Hangzhou, 310053, China

For all author emails, please log on.

Citation and License

BMC Cancer 2012, 12:290  doi:10.1186/1471-2407-12-290

Published: 16 July 2012

Abstract

Background

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.

Methods

The 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.

Results

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.

Conclusions

Overexpression 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.

Keywords:
ZIC1; Sonic hedgehog; Cell cycle; Tumour suppressor