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Wnt-5a has tumor suppressor activity in thyroid carcinoma
N Kremenevskaja1, R von Wasielewski, A S Rao
1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg Str. 1, D-30625 Hannover, Germany.
Oncogene
|March 1, 2005
Summary
Wnt-5a, a noncanonical Wnt pathway molecule, acts as a tumor suppressor in differentiated thyroid carcinomas. It inhibits proliferation and invasiveness by promoting beta-catenin phosphorylation, opposing canonical Wnt/beta-catenin signaling.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Canonical Wnt/beta-catenin signaling pathway activation, marked by beta-catenin stabilization, is linked to human carcinomas.
- Noncanonical Wnt signaling pathways also influence neoplastic transformation, but their roles are less understood.
- Wnt-5a is a key member of the noncanonical Wnt signaling pathway.
Purpose of the Study:
- To investigate the effects of Wnt-5a in primary thyroid carcinomas and cell lines.
- To determine the role of Wnt-5a in thyroid tumor development and progression.
Main Methods:
- Quantitative analysis of Wnt-5a mRNA expression in normal thyroid tissue and thyroid carcinomas.
- Immunohistochemical analysis of Wnt-5a protein expression in thyroid tumors.
- Wnt-5a gene transfection into FTC-133 thyroid tumor cells to assess proliferation, migration, and invasiveness.
- Analysis of beta-catenin and GSK-3 beta phosphorylation, intracellular calcium release, and downstream signaling pathways (CaMKII, PKC).
Main Results:
- Wnt-5a mRNA expression was significantly increased in thyroid carcinomas compared to normal tissue.
- Immunohistochemistry revealed a bell-shaped expression pattern: low in normal tissue and anaplastic tumors, high in differentiated thyroid carcinomas.
- Wnt-5a transfection reduced proliferation, migration, invasiveness, and clonogenicity of FTC-133 cells.
- Wnt-5a induced membranous beta-catenin translocation, c-myc suppression, and increased intracellular Ca(2+) release, promoting beta-catenin phosphorylation via CaMKII.
- Inhibition of beta-catenin phosphorylation by W-7 or KN-93 confirmed the CaMKII-dependent mechanism, while PKC inhibitors had no effect.
- Wnt-5a did not affect GSK-3 beta phosphorylation at Ser(9), indicating downstream action.
Conclusions:
- Wnt-5a exhibits tumor suppressor activity in differentiated thyroid carcinomas.
- Wnt-5a antagonizes the canonical Wnt/beta-catenin signaling pathway through promoting beta-catenin phosphorylation via a Ca(2+)/CaMKII-dependent mechanism.
- These findings highlight Wnt-5a as a potential therapeutic target in thyroid cancer.