p21 promotes sustained liver regeneration and hepatocarcinogenesis in chronic cholestatic liver injury
p21 promotes sustained liver regeneration and hepatocarcinogenesis in chronic cholestatic liver injury
复制标题
DOI：
10.1136/gutjnl-2013-304829
复制
发表时间：
2014-09-01
期刊：
影响因子：
24.5
通讯作者：
Vogel, Arndt
中科院分区：
文献类型：
--
作者：
Marhenke, Silke;Buitrago-Molina, Laura Elisa;Vogel, Arndt
背景和目的细胞周期蛋白依赖性激酶抑制剂p21被认为是一种肿瘤抑制剂。此外，最近的遗传学研究表明，p21可能是改善慢性疾病再生的潜在治疗靶点。本研究的目的是描绘p21在慢性肝损伤中的作用，并指定其在肝癌发生中的作用，在小鼠模型中的慢性胆汁淤积性liver injury.Methods的肝损伤，再生和肿瘤形成的程度进行了评估，在Mdr 2（-/-）小鼠和Mdr 2/p21（-/-）小鼠进行比较。结果Mdr 2（-/-）小鼠慢性炎症性肝损伤后发生肝细胞癌（HCC）。相比之下，Mdr 2/p21（-/-）小鼠的肿瘤发展明显延迟。在Mdr 2/p21（-/-）小鼠中，延迟的肿瘤发展伴随着明显受损的肝再生。此外，Mdr 2/p21（-/-）肝脏对部分肝切除的再生能力随着年龄的增长而下降。肝细胞移植实验表明，受损的肝再生是由于细胞内的内在因素和Mdr 2/p21（-/-）微环境的变化。在人类肝癌，肿瘤表达p21，这是与一个显着较短的患者survival.Conclusions的一个子集，我们提供的实验证据表明，p21是需要持续的肝再生和肿瘤的发展，在慢性肝损伤，p21需要严格监管，以平衡肝再生和癌症的风险。此外，我们确定p21作为人类HCC的阴性预后标志物。
Background and aims The cyclin-dependent kinase inhibitor p21 has been implicated as a tumour suppressor. Moreover, recent genetic studies suggest that p21 might be a potential therapeutic target to improve regeneration in chronic diseases. The aim of this study was to delineate the role of p21 in chronic liver injury and to specify its role in hepatocarcinogenesis in a mouse model of chronic cholestatic liver injury.Methods The degree of liver injury, regeneration and tumour formation was assessed in Mdr2(-/-) mice and compared with Mdr2/p21(-/-) mice. Moreover, the role of p21 was evaluated in hepatoma cells in vitro and in human hepatocellular carcinoma (HCC).Results Mdr2(-/-) mice developed HCCs as a consequence of chronic inflammatory liver injury. In contrast, tumour development was profoundly delayed in Mdr2/p21(-/-) mice. Delayed tumour development was accompanied by markedly impaired liver regeneration in Mdr2/p21(-/-) mice. Moreover, the regenerative capacity of the Mdr2/p21(-/-) livers in response to partial hepatectomy declined with age in these mice. Hepatocyte transplantation experiments revealed that impaired liver regeneration was due to intrinsic factors within the cells and changes in the Mdr2/p21(-/-) microenvironment. In human HCCs, a subset of tumours expressed p21, which was associated with a significant shorter patient survival.Conclusions We provide experimental evidence that p21 is required for sustained liver regeneration and tumour development in chronic liver injury indicating that p21 needs to be tightly regulated in order to balance liver regeneration and cancer risk. Moreover, we identify p21 as a negative prognostic marker in human HCC.