Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2004) 8 OC18

SFE2004 Oral Communications Young Endocrinologist Session (7 abstracts)

Regulation of canonical Wnt/beta-catenin signalling pathway plays a central role in the thyroid growth and proliferation in neoplastic thyroid cell lines

AS Rao , N Kremenevskaja , J Resch & G Brabant

Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.

The basic mechanisms underlying thyroid growth and proliferation in thyroid cancer are still incompletely characterized. Lithium inhibits GSK3beta and affects via phosphorylation the degradation of free beta-catenin, a potent transcription factor. Hence, using lithium as a model to modulate the wnt/beta-catenin pathway, we investigated its potential activation in-vitro in neoplastic human thyroid cell lines (FTC133, NPA).

Our results show that lithium functionally activates wnt/beta-catenin signalling by at least four mechanisms. First, lithium dose dependently inactivates the proteasome by more than fifty percent. Second, it inhibits GSK3beta via phosphorylation at serine-9 and stabilizes the free form of the active beta-catenin in a dose (1-20 millimolar) and time (0-24 hours) dependant manner. Third, E-cadherin expression is dose-dependently down-regulated by lithium (1-5 millimolar). Fourth, proliferation of the cells is significantly increased (MTT-proliferation assay) which appears to be mediated via nuclear translocation of stabilized beta-catenin (Reporter gene assay) and upregulation of cyclin D1 levels.

To characterize the specificity of a beta-catenin dependent effect on thyrocyte proliferation we transiently transfected FTC-133 cells with dominant negative TCF-4 (dnTCF-4) and dominant negative CREB (dnCREB) to block the wnt/beta-catenin and cAMP dependent pathways respectively. As lithium dependent stimulation of proliferation was still present in dnCREB FTC-133 cells and was reduced drastically in dnTCF-4 FTC133 cells, it seems plausible that thyrocyte proliferation is regulated by the wnt/beta-catenin signalling pathways and is not entirely dependent on cAMP signalling pathways. We further characterized in permanently transfected dnTCF4 cells the effects of recombinant human TSH, bovine TSH, EGF, IGF-1 and insulin on the thyroid growth, invasion and migration to elucidate the relevance of an active wnt/beta-catenin signalling pathway. Thus, our data indicate that regulation of wnt/beta-catenin plays a central role in the thyroid growth and lithium enhances the proliferative potency of the human thyroid cancer cell lines in-vitro by activiating its signalling.

Volume 8

195th Meeting of the Society for Endocrinology joint with Diabetes UK and the Growth Factor Group

Society for Endocrinology 

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