Aberrant localization of beta-catenin correlates with overexpression of its target gene in human papillary thyroid cancer.
Alterations of the Wnt/beta-catenin signaling pathway are known to occur in mutations of the component genes such as APC, Axin, and beta-catenin, and play a pathogenetic role in tumorigenesis. Activated Wnt signaling stabilizes beta-catenin, which associates with T cell factor, resulting in transactivation of the downstream target genes including c-myc and cyclin D1. To investigate the involvement of Wnt/beta-catenin signaling pathway in thyroid tumorigenesis, we analyzed its activation and localization in 5 human thyroid cancer cell lines and 132 thyroid tumor tissue samples. Dislocalization of beta-catenin was observed in all cell lines. Constitutive activation of T cell factor in two of four thyroid cancer cell lines was observed using reporter gene assay. Furthermore, high expression levels of c-Myc and cyclin D1 were observed in cell lines that showed cytoplasmic or nuclear accumulation of beta-catenin. In 132 paraffin-embedded thyroid carcinoma tissue samples, cytoplasmic beta-catenin was immunohistochemically observed in 52 out of 78 (67%) papillary thyroid cancers, but only in 3 of 34 (9%) follicular adenomas and 5 of 20 (25%) follicular cancers. Cytoplasmic localization of beta-catenin significantly correlated with overexpression of cyclin D1 in papillary carcinomas. Our results suggest that aberrant activation of Wnt/beta-catenin signaling is strongly involved in thyroid tumorigenesis.
Ishigaki
Katsu
K
Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, 1 -12-4 Sakamoto, Nagasaki 852-8523, Japan.
Namba
Hiroyuki
H
Nakashima
Masahiro
M
Nakayama
Toshiyuki
T
Mitsutake
Norisato
N
Hayashi
Tomayoshi
T
Maeda
Shigeto
S
Ichinose
Makoto
M
Kanematsu
Takashi
T
Yamashita
Shunichi
S
D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000378:metabolism; D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D060466:Axin Protein; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D011506:Proteins / Q000235:genetics; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism*; D014018:Tissue Distribution; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D051176:beta Catenin
C491761:AXIN2 protein, human; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D011506:Proteins; D012097:Repressor Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1