Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma
Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma
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DOI：
10.1038/sj.onc.1206926
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发表时间：
2004-01-08
期刊：
影响因子：
8
通讯作者：
Friess, H
中科院分区：
文献类型：
--
作者：
Guo, JC;Kleeff, J;Friess, H
胰腺导管腺癌(PDAC)是导致癌症相关死亡的主要原因之一。细胞周期调控的失控被认为是细胞恶性转化的关键事件，而CDC25磷酸酶是一类细胞周期蛋白依赖的激酶激活剂家族，作用于细胞周期的不同时间点，包括G1-S和G2-M转变。为此，我们研究了CDC25s在PDAC中的表达及其功能意义。采用基因芯片、定量聚合酶链式反应和Northern印迹分析CDC25B在人胰腺组织中的表达水平。免疫组织化学方法对CDC25B的表达进行定位和定量。使用两种特异性的CDC25B抑制剂来确定CDC25B的功能相关性。定量RT-PCR结果显示，CDC25B在胰腺癌组织中过度表达，是正常胰腺组织的7.5倍。CDC25B在胰腺癌和转移癌组织中均呈强阳性表达，其阳性细胞百分率在原发癌(48.6+/-16.3%)和转移癌(71.7+/-3.1%)明显高于正常组织(8.3+/-1.8%)。两种CDC25B抑制剂抑制胰腺癌细胞的生长，导致CDC2磷酸化和G2/M期停滞。这些发现证明了CDC25B在细胞周期进程中的重要作用，增加了抑制CDC25B可能对胰腺癌具有治疗潜力的可能性。
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Deregulation of cell-cycle control is thought to be a crucial event in malignant transformation, and CDC25 phosphatases are a family of cyclin-dependent kinase activators, which act at different points of the cell cycle, including G1-S and G2-M transition. Here, we investigated the expression and functional significance of CDC25s in PDAC. CDC25B mRNA expression levels in human pancreatic tissue samples were analysed by cDNA array, quantitative PCR and Northern blotting. Immunohistochemistry was carried out to localize and quantify CDC25B expression. Two specific CDC25B inhibitors were utilized to determine the functional relevance of CDC25B. By quantitative RT-PCR, CDC25B mRNA was overexpressed in pancreatic cancer (7.5-fold) in comparison to the normal pancreas. Strong nuclear CDC25B immunoreactivity was present in both pancreatic and metastatic cancer samples, and there was a marked increase of the percentage of positive cells in primary cancer (48.6+/-16.3%) and metastatic tissues (71.7+/-3.1%) compared to normal samples (8.3+/-1.8%). Two CDC25B inhibitors reduced the growth of pancreatic cancer cell lines, resulting in the accumulation of phosphorylated CDC2 and G2/M arrest. These findings demonstrate an important role of CDC25B in cell-cycle progression, raising the possibility that inhibition of CDC25B may have therapeutic potential in pancreatic cancer.