FOXM1 is a molecular determinant of the mitogenic and invasive phenotype of anaplastic thyroid carcinoma.
FOXM1 is a molecular determinant of the mitogenic and invasive phenotype of anaplastic thyroid carcinoma.
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DOI：
10.1530/erc-12-0031
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发表时间：
2012-10
影响因子：
3.9
通讯作者：
Santoro M
中科院分区：
文献类型：
--
作者：
Bellelli R;Castellone MD;Garcia-Rostan G;Ugolini C;Nucera C;Sadow PM;Nappi TC;Salerno P;Cantisani MC;Basolo F;Gago TA;Salvatore G;Santoro M
甲状腺未分化癌（ATC）是一种非常侵袭性的甲状腺癌。叉头盒蛋白M1（FOXM 1）是参与控制细胞增殖、染色体稳定性、血管生成和侵袭的转录因子的叉头盒家族的成员。在这里，我们发现FOXM 1在ATC中显著增加，与正常甲状腺、高分化甲状腺癌（乳头状和/或滤泡状）和低分化甲状腺癌相比（P=0.000002）。ATC细胞中FOXM 1水平的上调与p53功能丧失和磷脂酰肌醇-3-激酶/AKT/FOXO 3a通路的过度激活有机械联系。通过RNA干扰敲低FOXM 1通过将细胞阻滞在G2/M期来抑制细胞增殖，并降低细胞侵袭力和运动性。这种表型与FOXM 1靶基因表达降低相关，如细胞周期蛋白B1（CCNB 1）、polo样激酶1（PLK 1）、Aurora B（AURKB）、S期激酶相关蛋白2（SKP 2）和纤溶酶原激活剂尿激酶：uPA（PLAU）。在ATC的原位小鼠模型中，FOXM 1的药理学抑制降低了肿瘤负荷和转移。总之，这些发现表明FOXM 1在甲状腺癌向间变性表型的进展中起重要作用，并且是这种致命癌症的潜在治疗靶点。
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.