Genotype-phenotype relationships in hepatocellular tumors from mice and man
Genotype-phenotype relationships in hepatocellular tumors from mice and man
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DOI：
10.1002/hep.20768
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发表时间：
2005-08-01
期刊：
影响因子：
13.5
通讯作者：
Schwarz, M
中科院分区：
文献类型：
--
作者：
Stahl, S;Ittrich, C;Schwarz, M
根据致癌治疗，实验诱导的小鼠肝脏肿瘤包含Catnb(β-连环素)或Ha-ras的激活突变。我们现在已经通过微阵列分析研究了这两种基因在肿瘤中的表达谱。总共鉴定了364个相对于正常肝脏有异常表达的基因或表达序列，但其中只有30个在两种肿瘤类型中都显示出单向变化。一些功能簇被确定，涉及Camb突变肿瘤的氨基酸利用和氨处置的变化，而不是Ha-ras突变肿瘤的脂类和胆固醇代谢的变化。此外，在Catnb突变的肿瘤中，几个编码WRIT信号通路中抑制分子的基因上调，这表明诱导了一个负反馈环，而Ha-ras突变的肿瘤显示出几个在单体G蛋白信号转导中起作用的基因的表达发生了变化。我们得出结论，小鼠肝癌细胞采取不同的进化策略，允许它们在不同的环境条件下选择性生长。人肝细胞癌缺乏RAS突变，但在人类Catnb直系同源基因CTNNB1中经常发生突变。在Catnb突变的小鼠肿瘤中异常表达的一组基因被用来通过表达谱来筛选25个肝癌中的同源基因的失调，其中10个是CTNNB1突变的。具有激活的β3-连环蛋白的人肝细胞癌表现出类似于Camb突变的小鼠肿瘤的基因表达谱，但与其他人肝细胞癌不同。综上所述，表达指纹可用于诊断目的和潜在的新的治疗干预策略。
Experimentally induced liver tumors in mice harbor activating mutations in either Catnb (beta-catenin) or Ha-ras, according to the carcinogenic treatment. We have now investigated by microarray analysis the gene expression profiles in tumors of the two genotypes. In total, 364 genes or expressed sequences with aberrant expression relative to normal liver were identified, but only 30 of these demonstrated unidirectional changes in both tumor types. Several functional clusters were identified that involve changes in amino acid utilization and ammonia disposition in Camb-mutated tumors as opposed to alterations in lipid and cholesterol metabolism in Ha-ras-mutated tumors. Moreover, several genes coding for inhibitory molecules within the Writ-signaling pathway were upregulated in Catnb-mutated tumors, suggesting induction of a negative feedback loop, whereas Ha-ras-mutated tumors showed alterations in the expression of several genes functional in monomeric G-protein signaling. We conclude that mouse hepatoma cells adopt different evolutionary strategies that allow for their selective outgrowth under variable environmental conditions. Human hepatocellular cancers (HCC) lack RAS mutations but are frequently mutated in CTNNB1, the human Catnb ortholog. The set of genes aberrantly expressed in Catnb-mutated mouse tumors was used to screen, by expression profiling, for dysregulation of orthologous genes within a panel of 25 HCCs, of which 10 were CTNNB1-mutated. HCCs with activated beta 3-catenin displayed a gene expression profile that was similar to Camb-mutated mouse tumors but distinct from the other human HCCs. In conclusion, expression fingerprints may be used for diagnostic purposes and potential new therapeutic intervention strategies.