Overexpression of human Dickkopf-1, an antagonist of wingless/WNT signaling, in human hepatoblastomas and Wilms' tumors.
Hepatoblastomas (HBs) represent the most frequent malignant liver tumors of childhood; yet little is known about the molecular pathogenesis and the alterations in expression patterns of these tumors. We used a suppression subtractive hybridization approach to identify new candidate genes that may play a role in HB tumorigenesis. cDNA species derived from corresponding liver and fetal liver were subtracted from HB cDNAs, and a series of interesting candidates were isolated that were differentially expressed. One of the transcripts overexpressed in HB was derived from the human Dickkopf-1 (hDkk-1) gene, which encodes a secreted protein acting as a potent inhibitor of the wingless/WNT signaling pathway. We examined the hDkk-1 expression levels in 32 HB biopsy specimens and in the corresponding liver samples, in 4 HB cell lines, and in a panel of other tumors and normal tissues using a differential PCR approach and Northern blotting. Eighty-one percent of the HBs but none of the normal pediatric or fetal liver tissues showed hDkk-1 expression. hDkk-1 transcripts were also present in 5 of 6 Wilms' tumors but only weakly detectable in 2 of 20 hepatocellular carcinoma samples and in 1 of 5 medulloblastoma cell lines; transcripts were absent in malignant gliomas and breast cancer. The central effector molecule in the WNT developmental control pathway is the beta-catenin protein. Interestingly, activating mutations of the beta-catenin gene have previously been identified in 48% of HBs, and more than 85% of HBs show accumulation of beta-catenin protein as the indicator for an activated pathway. The overexpression of the inhibitor Dkk-1 may therefore be related to uncontrolled wingless/WNT signaling and may represent a negative feedback mechanism. hDkk-1 expression represents a novel marker for HBs and Wilms' tumors.
Wirths
Oliver
O
Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
Waha
Anke
A
Weggen
Sascha
S
Schirmacher
Peter
P
Kühne
Thomas
T
Goodyer
Cynthia G
CG
Albrecht
Steffen
S
Von Schweinitz
Dietrich
D
Pietsch
Torsten
T
D002675:Child, Preschool; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic; D005865:Gestational Age; D018197:Hepatoblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins; D029961:Zebrafish Proteins
C501126:DKK1 protein, human; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C501128:dkk1b protein, zebrafish