The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical course of epithelial ovarian cancer.
OBJECTIVE
Epithelial ovarian tumors (EOT) are among 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.


METHODS
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 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 EOTs.
Department of Oncology, Mario Negri Gynecological Oncology Group, Milano, Italy.
Sergio
S
Marchini
Elizabeth
E
Poynor
Richard R
RR
Barakat
Luca
L
Clivio
Michela
M
Cinquini
Robert
R
Fruscio
Luca
L
Porcu
Cecilia
C
Bussani
Maurizio
M
D'Incalci
Eugenio
E
Erba
Michela
M
Romano
Giorgio
G
Cattoretti
Dionyssios
D
Katsaros
Andrew
A
Koff
Lucio
L
Luzzatto
D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D009687:Nuclear Proteins; D014157:Transcription Factors; C492123:ZIC1 protein, human; C491812:ZIC2 protein, human