Regulation of Skp2-p27 axis by the Cdh1/anaphase-promoting complex pathway in colorectal tumorigenesis
Regulation of Skp2-p27 axis by the Cdh1/anaphase-promoting complex pathway in colorectal tumorigenesis
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DOI：
10.2353/ajpath.2008.070957
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发表时间：
2008-07-01
影响因子：
6
通讯作者：
Wan, Yong
中科院分区：
文献类型：
--
作者：
Fujita, Takeo;Liu, Weijun;Wan, Yong
进入S期是癌细胞的常见标志。Skp 2是泛素连接酶的一个亚基，对G（1）/S转换起着重要的调节作用。在人类肿瘤中经常检测到不受控制的Skp 2活性，通常与不良预后相关。目前的研究表明，Skp 2营业额的调节介导的另一个关键的泛素连接酶，后期促进复合物（APC），与其底物特异性因子Cdh 1。为了通过Skp 2的降解来剖析Cdh 1/APC在肿瘤发生中的潜在作用，我们使用人类肿瘤阵列和生化分析来分析Cdh 1/APC-Skp 2-p27轴在结直肠肿瘤发生中的作用。我们的研究结果表明，Cdh 1和p27阳性样品的百分比在结肠癌组织中显着低于在相邻的非恶性组织。相反，Skp 2阳性结肠癌样品的百分比显著高于正常组织。此外，从临床病理分析的结果显示，Cdh 1表达升高与较低的组织学分级肿瘤。此外，在非恶性结肠细胞中通过RNA干扰耗尽Cdh 1导致细胞增殖增加，而敲低Skp 2显著抑制癌细胞生长。我们的研究结果表明，Skp 2和Cdh 1/APC在结直肠癌的病理相关性。因此，Cdh 1可能通过Skp 2蛋白水解在结直肠肿瘤发生中发挥肿瘤抑制作用，并可能作为结肠癌患者的预后标志物。
Abrogated entry into S phase is a common hallmark of cancer cells. Skp2, a subunit of ubiquitin ligase, is critical for regulating the G(1)/S transition. Uncontrolled Skp2 activity is detected frequently in human tumors, often correlated with poor prognosis. Current studies have suggested that the regulation of Skp2 turnover is mediated by another critical ubiquitin ligase, the anaphase-promoting complex (APC), in association with its substrate-specific factor Cdh1. To dissect the potential role of Cdh1/APC in tumorigenesis through the degradation of Skp2, we analyzed the Cdh1/APC-Skp2-p27 axis in colorectal tumorigenesis using a human tumor array and biochemical analyses. Our results show that the percentage of Cdh1- and p27-positive samples in colon cancer tissues was significantly lower than that in adjacent nonmalignant tissue. Conversely, the percentage of Skp2-positive colon cancer samples was significantly higher than that in normal tissue. Furthermore, results from clinicopathological analysis revealed that elevated Cdh1 expression was associated with lower histological grade tumors. In addition, depletion of Cdh1 by RNA interference in nonmalignant colon cells resulted in increased cellular proliferation, whereas knockdown of Skp2 significantly suppressed cancer cell growth. Our result suggests a pathological correlation between Skp2 and Cdh1/APC in colorectal cancer. Thus, Cdh1 may function as a component in tumor suppression via proteolysis of Skp2 in colorectal tumorigenesis and may serve as a prognostic marker in colon cancer patients.