Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Gastroenterology. 2011 Oct;141(4):1439-50. doi: 10.1053/j.gastro.2011.06.046. Epub 2011 Jun 24.
BACKGROUND & AIMS: The tumor suppressors retinoblastoma (RB) and p53 are important regulators of the cell cycle. Although human cancer cells inactivate RB and p53 by many mechanisms, the cooperative roles of these proteins in tumorigenesis are complex and tissue specific. We analyzed the cooperation of RB and p53 in liver development and pathogenesis of hepatocellular carcinoma.
Spontaneous and carcinogen-induced (diethylnitrosamine) tumorigenesis were studied in mice with liver-specific deletions of Rb and/or p53 (Rbf/f;albcre+, p53f/f;albcre+ and Rbf/f; p53f/f;albcre+ mice). Genotype, histologic, immunohistochemical, microarray, quantitative polymerase chain reaction, immunoblot, and comparative genomic hybridization analyses were performed using normal and tumor samples. Comparative microarray analyses were performed against publicly available human microarray data sets.
Deletion of RB and p53 from livers of mice deregulated the transcriptional programs associated with human disease. These changes were not sufficient for spontaneous tumorigenesis; potent quiescence mechanisms compensated for loss of these tumor suppressors. In response to hepatocarcinogen-induced damage, distinct and cooperative roles of RB and p53 were revealed; their loss affected cell cycle control, checkpoint response, and genome stability. In damaged tissue, combined loss of RB and p53 resulted in early lesion formation, aggressive tumor progression, and gene expression signatures and histologic characteristics of advanced human hepatocellular carcinoma.
The effects RB and p53 loss are determined by the tissue environment; cell stresses that promote aggressive disease reveal the functions of these tumor suppressors.
肿瘤抑制因子视网膜母细胞瘤（RB）和 p53 是细胞周期的重要调节因子。尽管人类癌细胞通过多种机制使 RB 和 p53 失活，但这些蛋白质在肿瘤发生中的协同作用是复杂的且具有组织特异性。我们分析了 RB 和 p53 在肝脏发育和肝细胞癌发病机制中的协同作用。
研究了肝脏特异性缺失 Rb 和/或 p53（Rbf/f；albcre+、p53f/f；albcre+和 Rbf/f；p53f/f；albcre+小鼠）的自发性和致癌物（二乙基亚硝胺）诱导的肿瘤发生。使用正常和肿瘤样本进行了基因型、组织学、免疫组织化学、微阵列、定量聚合酶链反应、免疫印迹和比较基因组杂交分析。针对公开可用的人类微阵列数据集进行了比较微阵列分析。
从小鼠肝脏中缺失 RB 和 p53 会使与人类疾病相关的转录程序失调。这些变化不足以引起自发性肿瘤发生；强大的静止机制补偿了这些肿瘤抑制因子的缺失。在应对肝致癌物诱导的损伤时，揭示了 RB 和 p53 的独特和协同作用；它们的缺失影响细胞周期控制、检查点反应和基因组稳定性。在受损组织中，RB 和 p53 的联合缺失导致早期病变形成、侵袭性肿瘤进展以及基因表达谱和高级人类肝细胞癌的组织学特征。
RB 和 p53 缺失的影响取决于组织环境；促进侵袭性疾病的细胞应激揭示了这些肿瘤抑制因子的功能。
