DICKKOPF-4 and -2 genes are upregulated in human colorectal cancer.
To comprehensively screen for genetic events underlying colorectal cancer, we performed suppression subtraction hybridization analysis on an advanced colon cancer. Because Dickkopf-4, a member of the Dickkopf family acting as a Wnt-signaling modulator, was identified as one of the upregulated genes in this specimen, we investigated expression profiles of all the Dickkopf family members in 55 colorectal tumors (21 cancers and 34 adenomas). We also investigated mechanisms regulating the expression of Dickkopf-4 in these cancers in vitro and in vivo. Compared with normal adjacent mucosae, Dickkopf-4 (median 27.4, P < 0.01) and -2 (median 51.4, P < 0.01) were strongly expressed in colorectal cancers. The level of Dickkopf-4 was positively correlated with fibroblast growth factor-20 (r(s) = 0.61, P = 0.00017), a representative beta-catenin transcriptional target gene, and with the degree of nuclear accumulation of beta-catenin in colorectal tumors. Dickkopf-4 was induced by activated beta-catenin in vitro. Reciprocally, recombinant Dickkopf-4 significantly inhibited T-cell factor/lymphocyte enhancer factor reporter activity stimulated by recombinant Wnt3a in human embryonic kidney 293 cells. We conclude that Dickkopf-4 and -2 are significantly upregulated in most colorectal tumors, and that Dickkopf-4 upregulation reflects activation of the Wnt/canonical pathway.
Matsui
Akira
A
First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, Japan.
Yamaguchi
Tatsuya
T
Maekawa
Shinya
S
Miyazaki
Chikako
C
Takano
Shinichi
S
Uetake
Tomoyoshi
T
Inoue
Taisuke
T
Otaka
Masahiko
M
Otsuka
Hiroyuki
H
Sato
Tadashi
T
Yamashita
Atsuya
A
Takahashi
Yuka
Y
Enomoto
Nobuyuki
N
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D012372:ROC Curve; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; C498622:DKK2 protein, human; C442333:DKK4 protein, human; C416003:FGF20 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; D005346:Fibroblast Growth Factors