A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma.
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.
Salvatore
Giuliana
G
Dipartimento di Studi delle Istituzioni e dei Sistemi Territoriali, Universita' Parthenope, Naples, Italy.
Nappi
Tito Claudio
TC
Salerno
Paolo
P
Jiang
Yuan
Y
Garbi
Corrado
C
Ugolini
Clara
C
Miccoli
Paolo
P
Basolo
Fulvio
F
Castellone
Maria Domenica
MD
Cirafici
Anna Maria
AM
Melillo
Rosa Marina
RM
Fusco
Alfredo
A
Bittner
Michael L
ML
Santoro
Massimo
M
D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D043171:Chromosomal Instability; D006801:Humans; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C075840:TTK protein, human