TY - JOUR
T1 - FOXM1 is a molecular determinant of the mitogenic and invasive phenotype of anaplastic thyroid carcinoma
AU - Bellelli, Roberto
AU - Castellone, Maria Domenica
AU - Garcia-Rostan, Ginesa
AU - Ugolini, Clara
AU - Nucera, Carmelo
AU - Sadow, Peter M.
AU - Nappi, Tito Claudio
AU - Salerno, Paolo
AU - Cantisani, Maria Carmela
AU - Basolo, Fulvio
AU - Gago, Tomas Alvarez
AU - Salvatore, Giuliana
AU - Santoro, Massimo
PY - 2012/10
Y1 - 2012/10
N2 - Anaplastic thyroid carcinoma (ATC) is a very aggressive thyroid cancer. forkhead box protein M1 (FOXM1) is a member of the forkhead box family of transcription factors involved in control of cell proliferation, chromosomal stability, angiogenesis, and invasion. Here, we show that FOXM1 is significantly increased in ATCs compared with normal thyroid, well-differentiated thyroid carcinomas (papillary and/or follicular), and poorly differentiated thyroid carcinomas (P=0.000002). Upregulation of FOXM1 levels in ATC cells was mechanistically linked to loss-of-function of p53 and to the hyperactivation of the phosphatidylinositol-3-kinase/AKT/FOXO3a pathway. Knockdown of FOXM1 by RNA interference inhibited cell proliferation by arresting cells in G2/M and reduced cell invasion and motility. This phenotype was associated with decreased expression of FOXM1 target genes, like cyclin B1 (CCNB1), polo-like kinase 1 (PLK1), Aurora B (AURKB), S-phase kinase-associated protein 2 (SKP2 ), and plasminogen activator, urokinase: uPA ( PLAU). Pharmacological inhibition of FOXM1 in an orthotopic mouse model of ATC reduced tumor burden and metastasization. All together, these findings suggest that FOXM1 represents an important player in thyroid cancer progression to the anaplastic phenotype and a potential therapeutic target for this fatal cancer.
AB - Anaplastic thyroid carcinoma (ATC) is a very aggressive thyroid cancer. forkhead box protein M1 (FOXM1) is a member of the forkhead box family of transcription factors involved in control of cell proliferation, chromosomal stability, angiogenesis, and invasion. Here, we show that FOXM1 is significantly increased in ATCs compared with normal thyroid, well-differentiated thyroid carcinomas (papillary and/or follicular), and poorly differentiated thyroid carcinomas (P=0.000002). Upregulation of FOXM1 levels in ATC cells was mechanistically linked to loss-of-function of p53 and to the hyperactivation of the phosphatidylinositol-3-kinase/AKT/FOXO3a pathway. Knockdown of FOXM1 by RNA interference inhibited cell proliferation by arresting cells in G2/M and reduced cell invasion and motility. This phenotype was associated with decreased expression of FOXM1 target genes, like cyclin B1 (CCNB1), polo-like kinase 1 (PLK1), Aurora B (AURKB), S-phase kinase-associated protein 2 (SKP2 ), and plasminogen activator, urokinase: uPA ( PLAU). Pharmacological inhibition of FOXM1 in an orthotopic mouse model of ATC reduced tumor burden and metastasization. All together, these findings suggest that FOXM1 represents an important player in thyroid cancer progression to the anaplastic phenotype and a potential therapeutic target for this fatal cancer.
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U2 - 10.1530/ERC-12-0031
DO - 10.1530/ERC-12-0031
M3 - Article
C2 - 22919068
AN - SCOPUS:84867425304
SN - 1351-0088
VL - 19
SP - 695
EP - 710
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
IS - 5
ER -