Molecular Classification of Human and Mouse Hepatocellul

在c-myc/TGF-a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）。组织学上，在HCA结节中经常观察到小巢状的HCC，提示HCA在本模型中为恶性前病变。在本研究中，我们使用cDNA微阵列分析组织学明确的HCA和HCC肿瘤在分子水平上的差异。基因表达谱分析揭示了HCA和HCC之间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肿瘤的基因表达模式与HCA肿瘤相似。在被选择作为区分HCC和HCA肿瘤的潜在预测因子的几个基因中，通过RT-PCR重新检测了肿瘤中三个基因（Car3、Afp和Igfbp1）的表达。RT-PCR结果与基因芯片研究结果一致。血管生成素家族在HCC中的表达增强与肿瘤CD31免疫染色检测的HCC较高的血管生成状态一致。我们的研究表明，应用无偏分析方法对小鼠肿瘤的基因表达谱进行分析，可以更好地预测HCC和HCA的区别。基于HCA和HCC的基因表达谱，在该模型中鉴定出一组用于HCC发展过程中肿瘤分类的预测基因。此外，由抗原素家族表达引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.