Frequent deletions and mutations of the beta-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma.
Hepatoblastoma (HBL) is the most common malignant liver tumor in young children. Recent reports have shown that the beta-catenin gene was frequently mutated or deleted in HBLS: To elucidate the role of beta-catenin abnormalities in HBLs, we searched for mutations of beta-catenin and APC as well as expression of the target genes, cyclin D1, c-myc, and fibronectin, in 68 primary HBLS: The mutation analysis revealed that 44 (65%) tumors carried missense mutations or deletions of beta-catenin, all of which were somatic and targeted to the exon 3 encoding the amino acid residues involved in its degradation. However, no loss of function mutation of the APC gene was detected by the yeast functional assay. Of interest, beta-catenin mutation was significantly correlated with overexpression of the target genes, cyclin D1 and fibronectin, but not with that of c-myc in HBLs as measured by quantitative real-time reverse transcription-PCR. The immunohistochemical studies in 15 HBLs demonstrated that the nuclear/cytoplasmic accumulation of beta-catenin was positive in 13 tumors, 9 of which had the deletion or mutation of the gene. The significant correlation between the beta-catenin gene abnormality and the positive staining of cyclin D1 was also confirmed. Furthermore, the nuclear accumulation of beta-catenin was strongly associated with the poorly differentiated tumor cell components as well as with the positive staining of cyclin D1 within the tumor. Thus, our present results suggested that the gain of function mutation of beta-catenin played a crucial role in the malignant progression of HBL in vivo.
Takayasu
H
H
Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
Horie
H
H
Hiyama
E
E
Matsunaga
T
T
Hayashi
Y
Y
Watanabe
Y
Y
Suita
S
S
Kaneko
M
M
Sasaki
F
F
Hashizume
K
K
Ozaki
T
T
Furuuchi
K
K
Tada
M
M
Ohnuma
N
N
Nakagawara
A
A
D025601:Adenomatous Polyposis Coli Protein; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D019938:Cyclin D1 / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005353:Fibronectins / Q000378:metabolism*; D017353:Gene Deletion; D018197:Hepatoblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D013223:Statistics as Topic; D015534:Trans-Activators; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1