Expression of the Wnt antagonist DKK3 is frequently suppressed in sporadic epithelial ovarian cancer.
OBJECTIVE
The Wnt pathway plays an important role in embryonic development, and defects in this pathway have been implicated in the tumorigenesis. The Dickkopf 3 (DKK3) is a putative Wnt signaling inhibitor that is frequently inactivated in human cancers. However, the expression of DKK3 in ovarian cancer remains unknown.


METHODS
We investigated the expression of DKK3 in silico using the Digital Differential Display. DKK3 mRNA expression was also analyzed by real-time RT-PCR in ovarian carcinomas and normal ovarian tissues. DKK3 protein expression was determined by immunohistochemistry in the same ovarian carcinomas and normal ovarian tissues.


RESULTS
A significantly reduced expression of DKK3 (P < 0.05) was found after comparison of normal ovary- and tumor-derived libraries in the Cancer Genome Anatomy Project (CGAP). DKK3 mRNA expression was reduced in 63% (35 of 56) of tumors compared with normal ovarian samples (P < 0.02). Analysis of 13 matched pairs of ovarian carcinomas and adjacent normal tissues showed significant transcriptional downregulation of DKK3 (>twofold) in 9 paired carcinomas (69%). Loss or weak membranous expression of DKK3 protein was observed in 66% of ovarian cancers (37 of 56) including all tumors with low transcriptional level of DKK3 gene analyzed by real-time PCR.


CONCLUSIONS
To our best knowledge, this is the first time to demonstrate altered expression of DKK3 in ovarian cancer. The latter could be a relevant mechanism for the activation of the Wnt pathway in the carcinogenesis of ovarian cancer but additional studies are required to elucidate the function of DKK3 silencing in ovarian carcinogenesis.
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An
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Department of Radiotherapy and Radiation Oncology, Philipps-University Marburg, Baldingerstrasse, 35043 Marburg, Germany.
Fokas
Emmanouil
E
Wang
Lin-Fang
LF
He
Haitao
H
Kleb
Beate
B
Niederacher
Dieter
D
Engenhart-Cabillic
Rita
R
An
Han-Xiang
HX
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000077216:Carcinoma, Ovarian Epithelial; D018925:Chemokines; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism; D010053:Ovary / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins