Loss of p27Kip1 enhances tumor progression in chronic hepatocyte injury-induced liver tumorigenesis with widely ranging effects on Cdk2 or Cdc2 activation.
Loss of p27Kip1 enhances tumor progression in chronic hepatocyte injury-induced liver tumorigenesis with widely ranging effects on Cdk2 or Cdc2 activation.
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p27Kip1 的缺失会增强慢性肝细胞损伤诱导的肝脏肿瘤发生中的肿瘤进展，并对 Cdk2 或 Cdc2 激活产生广泛的影响。
DOI：
10.1093/carcin/bgm079
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发表时间：
2007
期刊：
影响因子：
4.7
通讯作者：
Zhu,Liang
中科院分区：
文献类型：
--
作者：
Sun,Daqian;Ren,Hao;Oertel,Michael;Sellers,RaniS;Zhu,Liang
p27Kip1失活对肿瘤发生的影响取决于所使用的小鼠模型，从促进到预防各不相同。当p27失活对肿瘤发生有积极作用时，由于p27作为Cdks抑制剂的功能已被确定，通常认为细胞周期蛋白依赖性激酶（cyclin-dependent kinase, Cdks）的去调控激活是潜在的机制。在这里，我们确定了p27失活对小鼠肝脏肿瘤发生过程中疾病进展和Cdk激活的影响，这种肿瘤起源于慢性肝损伤反应中的肝细胞再生增殖，这是大多数人类肝癌的既定病因。我们的研究结果表明，p27的失活不影响早期肝细胞再生增殖，但在疾病晚期促进肿瘤细胞增殖和进展。有趣的是，无论p27状态如何，Cdc2在所有晚期肿瘤中都过表达，而cyclin E1在一半的晚期肿瘤中都过表达；p27失活仅在一半的p27缺陷肿瘤中导致Cdk2或Cdc2的显著激活。这些结果揭示了p27在慢性肝细胞损伤诱导的肝肿瘤发生中的抑瘤作用，同时还需要进一步研究p27失活促进肿瘤发生的机制。
Effects of p27Kip1 inactivation on tumorigenesis vary from promotion to prevention dependent on the mouse models used. When p27 inactivation has a positive effect on tumorigenesis, de-regulated activation of cyclin-dependent kinases (Cdks) is generally believed to be the underlying mechanism since the function of p27 as an inhibitor of Cdks is firmly established. Here, we determined the effects of p27 inactivation on disease progression and Cdk activation in mouse liver tumorigenesis that originates from hepatocyte regenerative proliferation in response to chronic liver injury, an established etiology in most human liver cancer. Our results show that inactivation of p27 did not affect early-stage hepatocyte regenerative proliferation but promoted tumor cell proliferation and progression in the late stage of the disease. Interestingly, Cdc2 over-expression was observed in all and cyclin E1 was over-expressed in half of the late-stage tumors regardless of p27 status; and p27 inactivation led to significant activation of Cdk2 or Cdc2 only in half of the p27-deficient tumors. These results reveal a tumor suppressor role of p27 in chronic hepatocyte injury-induced liver tumorigenesis and, at the same time, the need to further study the mechanisms for tumor promotion by p27 inactivation.