Aberrant activation of ERK/FOXM1 signaling cascade triggers the cell migration/invasion in ovarian cancer cells.
Aberrant activation of ERK/FOXM1 signaling cascade triggers the cell migration/invasion in ovarian cancer cells.
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DOI：
10.1371/journal.pone.0023790
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Ngan HY
中科院分区：
文献类型：
--
作者：
Lok GT;Chan DW;Liu VW;Hui WW;Leung TH;Yao KM;Ngan HY
叉头盒M1 （FOXM1）是细胞周期进程中必不可少的增殖相关转录因子。大量研究证明FOXM1在肿瘤发生中具有多种功能，其水平升高通常与癌症进展有关。在这里，我们描述了ERK/FOXM1信号在介导卵巢癌细胞转移潜能中的作用。免疫组化（IHC）、免疫印迹（immunoblotting）和半定量RT-PCR分析发现，phospho-ERK和FOXM1在卵巢癌中经常上调。有趣的是，过表达的phospho-ERK （p<0.001）和FOXM1 （p<0.001）与具有侵袭性行为（如淋巴结转移）的高级别卵巢肿瘤（5 / 6）显著相关。phospho-ERK与FOXM1的表达呈显著正相关（p<0.001）。功能上，FOXM1B异位表达显著增强细胞迁移/侵袭，而FOXM1C不仅增加细胞增殖，而且促进细胞迁移/侵袭。相反，巯基链霉素或U0126抑制FOXM1表达可显著损害FOXM1介导的致癌能力。然而，无论是硫链霉素还是U0126对FOXM1的下调都需要p53在卵巢癌细胞中的存在。总的来说，我们的数据表明FOXM1的过表达可能源于构成活性的ERK，它赋予卵巢癌细胞转移能力。FOXM1抑制剂对癌细胞转移潜能的损害强调了其在晚期卵巢肿瘤中的治疗价值。
Forkhead box M1 (FOXM1) is a proliferation-associated transcription factor essential for cell cycle progression. Numerous studies have documented that FOXM1 has multiple functions in tumorigenesis and its elevated levels are frequently associated with cancer progression. Here, we characterized the role of ERK/FOXM1 signaling in mediating the metastatic potential of ovarian cancer cells. Immunohistochemical (IHC), immunoblotting and semi-quantitative RT-PCR analyses found that both phospho-ERK and FOXM1 were frequently upregulated in ovarian cancers. Intriguingly, the overexpressed phospho-ERK (p<0.001) and FOXM1 (p<0.001) were significantly correlated to high-grade ovarian tumors with aggressive behavior such as metastasized lymph node (5 out of 6). Moreover, the expressions of phospho-ERK and FOXM1 had significantly positive correlation (p<0.001). Functionally, ectopic expression of FOXM1B remarkably enhanced cell migration/invasion, while FOXM1C not only increased cell proliferation but also promoted cell migration/invasion. Conversely, inhibition of FOXM1 expression by either thiostrepton or U0126 could significantly impair FOXM1 mediated oncogenic capacities. However, the down-regulation of FOXM1 by either thiostrepton or U0126 required the presence of p53 in ovarian cancer cells. Collectively, our data suggest that over-expression of FOXM1 might stem from the constitutively active ERK which confers the metastatic capabilities to ovarian cancer cells. The impairment of metastatic potential of cancer cells by FOXM1 inhibitors underscores its therapeutic value in advanced ovarian tumors.
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