Disruption of Trp53 in Livers of Mice Induces Formation of Carcinomas With Bilineal Differentiation
Disruption of Trp53 in Livers of Mice Induces Formation of Carcinomas With Bilineal Differentiation
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DOI：
10.1053/j.gastro.2012.02.009
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发表时间：
2012-05-01
期刊：
影响因子：
29.4
通讯作者：
Rudolph, K. Lenhard
中科院分区：
文献类型：
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作者：
Katz, Sarah-Fee;Lechel, Andre;Rudolph, K. Lenhard
背景与目的：p53限制了来自各种组织的干细胞的自我更新。p53的缺失，与其他致癌事件相结合，导致异常的自我更新和祖细胞的转化。目前尚不清楚p53的缺失是否足以诱导肝脏中的肿瘤形成。方法：我们使用AlfpCre小鼠来产生具有肝脏特异性Trp 53破坏的小鼠（AlfpCre（+）Trp 53（Delta 2-10/Delta 2-10）小鼠）。我们分析了集落形成和基因组特征和基因表达模式在肝癌发生过程中的小鼠与纯合子，杂合子，和没有中断的Trp 53。结果：肝特异性Trp 53的破坏一致诱导形成具有双线性分化的肝癌。在未转化的肝细胞和培养的原代肝细胞中，p53（而不是p21）的丢失导致染色体失衡和肝祖细胞（LPC）和肝细胞的克隆形成能力增加。来自AlfpCre（+）Trp 53（Delta 2-10/Delta 2-10）小鼠而非Cdkn 1a（-/-）小鼠的肝细胞和LPC的原代培养物在移植到免疫功能低下的小鼠中时形成了具有双线分化的肿瘤。在AlfpCre（+）Trp 53（Delta 2-10/Delta 2-10）小鼠中发生的自发性肝肿瘤与野生型Trp 53小鼠发生的化学诱导肝肿瘤相比，Rb检查点基因的表达发生了显著但复杂的变化。结论：从小鼠肝脏中缺失p53足以诱导肿瘤形成。该肿瘤具有双线分化和Rb检查点基因失调。
BACKGROUND & AIMS: p53 limits the self-renewal of stem cells from various tissues. Loss of p53, in combination with other oncogenic events, results in aberrant self-renewal and transformation of progenitor cells. It is not known whether loss of p53 is sufficient to induce tumor formation in liver. METHODS: We used AlfpCre mice to create mice with liver-specific disruption of Trp53 (AlfpCre(+)Trp53(Delta 2-10/Delta 2-10) mice). We analyzed colony formation and genomic features and gene expression patterns in liver cells during hepatocarcinogenesis in mice with homozygous, heterozygous, and no disruption of Trp53. RESULTS: Liver-specific disruption of Trp53 consistently induced formation of liver carcinomas that had bilineal differentiation. In nontransformed liver cells and cultured primary liver cells, loss of p53 (but not p21) resulted in chromosomal imbalances and increased clonogenic capacity of liver progenitor cells (LPCs) and hepatocytes. Primary cultures of hepatocytes and LPCs from AlfpCre(+)Trp53(Delta 2-10/Delta 2-10) mice, but not Cdkn1a(-/-) mice, formed tumors with bilineal differentiation when transplanted into immunocompromised mice. Spontaneous liver tumors that developed in AlfpCre(+)Trp53(Delta 2-10/Delta 2-10) mice had significant but complex alterations in expression of Rb checkpoint genes compared with chemically induced liver tumors that developed mice with wild-type Trp53. CONCLUSIONS: Deletion of p53 from livers of mice is sufficient to induce tumor formation. The tumors have bilineal differentiation and dysregulation of Rb checkpoint genes.