The Zinc Finger Gene ZIC2 Has Features of an Oncogene and Its Overexpression Correlates Strongly with the Clinical Course of Epithelial Ovarian Cancer

Abstract

Purpose Epithelial ovarian tumors (EOTs) are amongst the most lethal of malignancies in women. We have previously identified ZIC2 as expressed at a higher level in samples of a malignant form (MAL) of EOT than in samples of a form with low malignant potential (LMP). We have now investigated the role of ZIC2 in driving tumor growth and its association with clinical outcomes. Experimental Design ZIC2 expression levels were analysed in two independent tumor tissue collections of LMP and MAL. In vitro experiments aimed to test the role of ZIC2 as a transforming gene. Cox models were used to correlate ZIC2 expression with clinical endpoints. Results ZIC2 expression was about 40-fold in terms of mRNA and about 17-fold in terms of protein in MAL (n = 193) versus LMP (n = 39) tumors. ZIC2 mRNA levels were high in MAL cell lines, but undetectable in LMP cell lines. Over-expression of ZIC2 was localized to the nucleus. ZIC2 over-expression increases the growth rate and foci formation of NIH 3T3 cells, and stimulates anchorage-independent colony formation; down-regulation of ZIC2 decreases the growth rate of MAL cell lines. Zinc finger domains 1 and 2 are required for transforming activity. In stage I MAL ZIC2 expression was significantly associated with overall survival in both univariate (p = 0.046), and multivariate model (p = 0.049). Conclusions ZIC2, a transcription factor related to the sonic hedgehog pathway, is a strong discriminant between MAL and LMP tumors: it may be a major determinant of outcome of EOT.

Gene Signature in Sessile Serrated Polyps Identifies Colon Cancer Subtype

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ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells

“…In both mice and humans, heterozygous deletions or other mutations of ZIC2 cause severe brain malformation, indicating its critical role in the development of the CNS (17). ZIC2 has been reported to be highly expressed in some tumors and implicated in tumorigenesis (18,19). However, how ZIC2 regulates liver cancer and liver CSCs remains elusive.…”

Hedgehog signalling network gene status analysis in paediatric intracranial germ cell tumours

“…It is one of the most important factors affecting neural tube development, cell differentiation and proliferation. ZIC2 alterations have been connected to pathogenesis and progression of some tumours [7,8,13,24,30]. Another candidate gene, located at chromosome 13q and hence notoriously affected by GCTs, is FGF9.…”