Sun Daqian, Ren Hao, Oertel Michael, Sellers Rani S, Shafritz David A, Zhu Liang
Department of Developmental and Molecular Biology, Marion Bessin Liver Research Center and Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Mol Carcinog. 2008 Jan;47(1):47-55. doi: 10.1002/mc.20360.
The biochemical function of p27Kip1 as an inhibitor of cyclin-dependent kinases is well-established, but the role of p27 as a tumor suppressor depends on specific cellular contexts. Previous studies using p27 knockout mice on mixed C57BL/6J x 129/Sv strain background did not find a tumor suppressor role of p27 in the liver. An important feature of mouse liver tumorigenesis is strain-dependent tumor susceptibility. Here, we determined the role of p27 in liver tumorigenesis in C57BL/6J mice, a liver tumor resistant strain, in response to a diethylnitrosamine (DEN) and phenolbarbital (PB) two-stage carcinogenesis protocol. At 6 mo of age, while livers of DEN-PB treated p27+/+ and p27-/- C57BL/6J mice appeared morphologically normal, p27-/- livers, but not p27+/+ livers, contained readily detectable glucose-6-phosphatase (G6Pase)-deficient foci. At the 9-mo time point, p27-/- mice developed significantly enhanced liver tumor phenotypes than p27+/+ mice as demonstrated by increased numbers and sizes of liver surface nodules, increased liver-to-body weight ratios, and increased numbers of G6Pase-deficient nodules and histologically diagnosed foci and adenomas in liver sections. Hepatic lesions in p27-/- livers contained more proliferating hepatocytes than lesions in p27+/+ livers, while the numbers of apoptotic cells appeared similar in lesions of both genotypes. Unexpectedly, tumors in p27-/- livers contained only slightly elevated Cdk2 kinase activity compared with normal livers. These results reveal a liver tumor suppressor role of p27 in this resistant mouse strain, and the need to further study the role of Cdk2 kinase in liver tumor promotion by p27 inactivation.
p27Kip1作为细胞周期蛋白依赖性激酶抑制剂的生化功能已得到充分证实，但p27作为肿瘤抑制因子的作用取决于特定的细胞环境。先前在混合的C57BL/6J x 129/Sv品系背景下使用p27基因敲除小鼠的研究未发现p27在肝脏中具有肿瘤抑制作用。小鼠肝脏肿瘤发生的一个重要特征是品系依赖性肿瘤易感性。在此，我们确定了p27在C57BL/6J小鼠（一种肝脏肿瘤抗性品系）肝脏肿瘤发生中的作用，该小鼠对二乙基亚硝胺（DEN）和苯巴比妥（PB）两阶段致癌方案有反应。在6月龄时，虽然经DEN-PB处理的p27+/+和p27-/- C57BL/6J小鼠的肝脏在形态上正常，但p27-/-小鼠的肝脏中含有易于检测到的葡萄糖-6-磷酸酶（G6Pase）缺陷灶，而p27+/+小鼠的肝脏中则没有。在9月龄时，p27-/-小鼠比p27+/+小鼠表现出明显增强的肝脏肿瘤表型，表现为肝脏表面结节的数量和大小增加、肝脏与体重比增加、G6Pase缺陷结节的数量增加以及肝脏切片中组织学诊断的病灶和腺瘤数量增加。p27-/-小鼠肝脏中的肝损伤比p27+/+小鼠肝脏中的损伤含有更多增殖的肝细胞，而两种基因型损伤中的凋亡细胞数量似乎相似。出乎意料的是，与正常肝脏相比，p27-/-小鼠肝脏中的肿瘤仅含有略微升高的Cdk2激酶活性。这些结果揭示了p27在这种抗性小鼠品系中的肝脏肿瘤抑制作用，以及进一步研究Cdk2激酶在p27失活促进肝脏肿瘤中的作用的必要性。
