The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical course of epithelial ovarian cancer

Sergio Marchini, Elizabeth Poynor, Richard R. Barakat, Luca Clivio, Michela Cinquini, Robert Fruscio, Luca Porcu, Cecilia Bussani, Maurizio D'Incalci, Eugenio Erba, Michela Romano, Giorgio Cattoretti, Dionyssios Katsaros, Andrew Koff, Lucio Luzzatto

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Abstract

Purpose: Epithelial ovarian tumors (EOT) are among the most lethal of malignancies in women.Wehave 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 analyzed 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. Overexpression of ZIC2 was localized to the nucleus. ZIC2 overexpression increases the growth rate and foci formation of NIH3T3 cells and stimulates anchorage-independent colony formation; downregulation of ZIC2 decreases the growth rate ofMALcell 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 EOTs.

Original languageEnglish
Pages (from-to)4313-4324
Number of pages12
JournalClinical Cancer Research
Volume18
Issue number16
DOIs
Publication statusPublished - Aug 15 2012

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Marchini, S., Poynor, E., Barakat, R. R., Clivio, L., Cinquini, M., Fruscio, R., Porcu, L., Bussani, C., D'Incalci, M., Erba, E., Romano, M., Cattoretti, G., Katsaros, D., Koff, A., & Luzzatto, L. (2012). The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical course of epithelial ovarian cancer. Clinical Cancer Research, 18(16), 4313-4324. https://doi.org/10.1158/1078-0432.CCR-12-0037