Abstract
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 (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.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.
Highlights
ZIC1, a vital transcription factor with zinc finger domains, has been implicated in the process of neural development
These data suggest that ectopic expression of ZIC1 suppresses gastric cancer cell migration and invasion
We demonstrated that the expression level of cyclin D1 protein was reduced while p21 and p27 were markedly induced in gastric cancer cells transfected with pCDNA3.1-ZIC1 when compared to those pCDNA3.1 empty vector transfectants (Figure 2B)
Summary
ZIC1, a vital transcription factor with zinc finger domains, has been implicated in the process of neural development. The molecular mechanism underlying ZIC1 participation in tumour progression remains unknown. ZIC1 has been documented to participate in the progression of human tumours including medulloblastoma, endometrial cancers, mesenchymal neoplasms and liposarcoma cancers [3,4,5,6]. We have previously shown that ZIC1 gene is significantly downregulated in gastric cancer tissues and Gastric cancer is the second leading cause of cancerrelated death worldwide [10,11]. It has been reported that ZIC1 could reduce the expression of PTCH1 and Shh genes in neural tissue during forebrain development [17]. Evidence has shown that the Shh represses the expression of ZIC1 during neural tube development [18]. The influence of ZIC1 on the Hh signaling pathway in gastric cancer remains unknown
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