Abstract
Here, we show that the anaplastic thyroid carcinoma (ATC) features the up-regulation of a set of genes involved in the control of cell cycle progression and chromosome segregation. This phenotype differentiates ATC from normal tissue and from well-differentiated papillary thyroid carcinoma. Transcriptional promoters of the ATC up-regulated genes are characterized by a modular organization featuring binding sites for E2F and NF-Y transcription factors and cell cycle-dependent element (CDE)/cell cycle gene homology region (CHR) cis-regulatory elements. Two protein kinases involved in cell cycle regulation, namely, Polo-like kinase 1 (PLK1) and T cell tyrosine kinase (TTK), are part of the gene set that is up-regulated in ATC. Adoptive overexpression of p53, p21 (CIP1/WAF1), and E2F4 down-regulated transcription from the PLK1 and TTK promoters in ATC cells, suggesting that these genes might be under the negative control of tumor suppressors of the p53 and pRB families. ATC, but not normal thyroid, cells depended on PLK1 for survival. RNAi-mediated PLK1 knockdown caused cell cycle arrest associated with 4N DNA content and massive mitotic cell death. Thus, thyroid cell anaplastic transformation is accompanied by the overexpression of a cell proliferation/genetic instability-related gene cluster that includes PLK1 kinase, which is a potential molecular target for ATC treatment.
Highlights
Anaplastic thyroid carcinoma (ATC) is a highly malignant tumor that accounts for 2% to 5% of all thyroid cancers and is usually seen in the sixth to seventh decades of life
Proliferation- and chromosomal instability-associated genes are up-regulated in ATC
This study shows that ATC is characterized by the overexpression of genes associated with cell proliferation and chromosomal instability
Summary
Anaplastic thyroid carcinoma (ATC) is a highly malignant tumor that accounts for 2% to 5% of all thyroid cancers and is usually seen in the sixth to seventh decades of life. ATC shares genetic alterations with welldifferentiated papillary (PTC) and follicular thyroid carcinomas, namely, point mutations in RAS and BRAF [1,2,3,4] and point mutations or gene amplification of PIK3CA [5, 6], suggesting that it may derive from a preexisting differentiated lesion. Whereas welldifferentiated thyroid carcinomas are rarely (
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