Disruption of Trp53 in Livers of Mice Induces Formation of Carcinomas With Bilineal Differentiation

作者：Katz Sarah Fee; Lechel Andre; Obenauf Anna C; Begus Nahrmann Yvonne; Kraus Johann M; Hoffmann Eva M; Duda Johanna; Eshraghi Parisa; Hartmann Daniel; Liss Birgit; Schirmacher Peter; Kestler Hans A; Speicher Michael R; Rudolph K Lenhard^*

来源：Gastroenterology, 2012, 142(5): 1229-+.

DOI：10.1053/j.gastro.2012.02.009

• Liver Cancer
• Cancer Stem Cell
• Tumor Suppressor

BACKGROUND %26 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.

• 出版日期2012-5