Molecular Classification of Human and Mouse Hepatocellul

在c-myc/TGF-α转基因小鼠模型中，肝细胞腺瘤（HCA）在4月龄时出现在肝脏中，并在8-10月龄时进展为肝细胞癌（HCC）。在组织学上，HCA结节中经常观察到小的HCC巢，表明HCA在该模型中是癌前病变。在本研究中，我们使用cDNA微阵列技术从分子水平上分析了组织学明确的HCA和HCC肿瘤之间的差异。基因表达谱分析显示HCA和HCC之间有不同的基因表达模式。有趣的是，一个HCA肿瘤的基因表达模式与HCC肿瘤相似，两个HCC肿瘤与HCA肿瘤相似。在选择作为区分HCC与HCA肿瘤的潜在预测因子的几个基因中，通过RT-PCR重新检查三个基因（Car 3、Afp和Igfbp 1）在肿瘤中的表达。RT-PCR结果与基因芯片结果一致。HCC中血管生成素家族的表达增强与通过肿瘤的CD 31免疫染色测量的HCC中较高的血管生成状态一致。我们的研究表明，无偏分析方法的应用，小鼠肿瘤的基因表达谱为我们提供了更好的预测时，区分肝癌和HCA。在此模型中，基于HCA和HCC的基因表达谱，鉴定了一组用于HCC发展期间肿瘤分类的预测基因。此外，由抗原原蛋白家族的表达触发的血管生成似乎是HCA向HCC转化过程中最关键的事件。

In the c-myc/TGF-a transgenic mouse model, hepatocellular adenoma (HCA) appear in the liver by 4 months of age and progresses to hepatocellular carcinoma (HCC) by 8-10 months of age. Histologically, a small nest of HCC are frequently observed in HCA nodules, suggesting that HCA is a pre-malignant lesion in this model. In this study we have used cDNA microarray to analyze the difference between histologically well-defined HCA and HCC tumors in molecular level. Gene expression profile analysis revealed distinctive gene expression patterns between HCA and HCC. Interestingly, gene expression pattern of one HCA tumor was similar to HCC tumors, and two HCC tumors similar to HCA tumors. Among several genes selected as potential predictors for distinguishing HCC from HCA tumors, expression of three genes (Car3, Afp, and Igfbp1) in tumors were re-examined by RT-PCR. RT-PCR results were consistent with the observation in cDNA microarray studies. Enhanced expression of angiogenin family in HCC is consistent with higher angiogenic status in HCC measured by CD31 immunostaining of tumors. Our study demonstrates that the application of unbiased analytical approaches to the gene expression profiles of mouse tumors provide us better prediction when distinguishing HCC from HCA. A set of predictor genes for the classification of tumors during development of HCC in this model was identified based on gene expression profiles of HCA and HCC. In addition, angiogenesis triggered by expression of antiogenin family appears to be the most critical event during conversion of HCA to HCC.