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Aberrant Localization of ß-Catenin Correlates with Overexpression of Its Target Gene in Human Papillary Thyroid Cancer

Department of Molecular Medicine (K.I., H.N., N.M., S.Y.), Tissue and Histopathology Section (M.N.), Division of Scientific Data Registry, Department of Molecular Pathology, Atomic Bomb Disease Institute (T.N.), Departments of Pathology (T.H.) and Surgery II (K.I., S.M., T.K.), Nagasaki University School of Medicine, Nagasaki 852-8523, Japan; and Department of Nutrition and Health Sciences (M.I.), Siebold University of Nagasaki, Nagayo 851-2195, Japan

Address all correspondence and requests for reprints to: A/Prof. Hiroyuki Namba, M.D., Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. E-mail: . namba{at}net.nagasaki-u.ac.jp

Abstract

Alterations of the Wnt/ß-catenin signaling pathway are known to occur in mutations of the component genes such as APC, Axin, and ß-catenin, and play a pathogenetic role in tumorigenesis. Activated Wnt signaling stabilizes ß-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/ß-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 ß-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 ß-catenin. In 132 paraffin-embedded thyroid carcinoma tissue samples, cytoplasmic ß-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 ß-catenin significantly correlated with overexpression of cyclin D1 in papillary carcinomas. Our results suggest that aberrant activation of Wnt/ß-catenin signaling is strongly involved in thyroid tumorigenesis.

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