Molecular mechanisms of progression and metastasis of hepatocellular carcinoma and their application on diagnosis and therapy.

在总共980个肝细胞癌结节中，我们回顾分析了肝细胞癌多步骤和多中心发展与潜在慢性肝病类型的关系。在980个结节中，369个(37.7%)符合多步骤肝癌的诊断标准。在664例患者中，177例(26.7%)有符合多中心肝细胞癌诊断标准的多发结节。多步和多中心肝细胞癌在丙型肝炎病毒抗体阳性病例中的发生率明显高于HBs-Ag阳性病例，我们比较了7种早期成分和7种进展成分在“结节中结节”型肝癌组织中的表达情况。在分析的大约12600个基因中，一组95个基因提供了区分早期肝细胞癌组成部分和非癌肝组织的分子特征，以及一组92个基因区分了进展期和早期肝细胞癌组成部分。在这些基因中，在肝细胞癌早期成分中表达最丰富的基因是热休克蛋白70(HSP70)。实时定量…更定量的RT-PCR证实了这一发现。进一步的免疫组织化学检测发现HSP70在早期肝细胞癌与癌前病变、进展期肝细胞癌与早期肝细胞癌相比均有显著的过度表达，对早期肝细胞癌的分子诊断有一定的价值。在分析的大约12600个基因中，我们确定了39个基因的表达水平与转移能力显著相关。在这些基因中，我们进一步研究了Cortactin。首先，我们证明了在非转移性肝癌细胞系中，Cortactin的过表达增加了细胞的活力，而在转移性肝癌细胞系中，Cortactin的沉默降低了细胞的活力，而在非转移性肝癌细胞系中，Cortactin的过表达导致了体内的转移。此外，免疫组织化学检测显示，在有肝内转移的肝细胞癌组织中，与无肝内转移的肝细胞癌相比，皮质蛋白的表达明显增强。较少

We retrospectively analyzed the relationship between multistep and multicentric development of HCC and the type of underlying chronic liver disease in a total of 980 HCC nodules. Of the 980 nodules, 369 (37.7%) met the criteria of multistep HCC. Of the 664 patients, 177(26.7%) had multiple nodules that met the criteria of multicentric HCC. Both the incidences of multistep and multicentric HCC were significantly higher in HCV-Ab-positive cases than in HBs-Ag-positive cases.We compared expression profiles among 7 early components and 7 progressed components of "nodule-in-nodule"-type HCC tissues. Of the approximately 12600 genes that were analyzed, a set of 95 genes provided a molecular signature that distinguished between early HCC components and their non-cancerous liver tissues, and a set of 92 genes distinguished between progressed and early HCC components. Of these genes, the most abundantly upregulated gene in early HCC components was heat-shock protein 70 (HSP70). Real-time quanti … More tative RT-PCR confirmed this finding. Further immunohistochemical examination of HSP70 revealed its significant overexpression in early HCC compared with precancerous lesions, and in progressed HCC compared with early HCC, and its usefulness for the molecular diagnosis of early HCC.We compared expression profiles among 2 highly metastatic HCC cell lines and 3 nonmetastatic HCC cell lines using oligonucleotide array. Of the approximately 12600 genes that were analyzed, we identified 39 genes whose expression levels were significantly correlated with metastatic ability. Of these genes, we further investigated cortactin. First, we demonstrated that overexpression of cortactin in nonmetastatic HCC cell line increased cell motility and silencing of cortactin in metastatic HCC cell line reduced cell motility, and overexpression of cortactin in nonmetastatic HCC cell line resulted in metastasis in vivo. Furthermore immunohistochemical examination of cortactin in human HCC samples revealed its significant overexpression in HCC with intrahepatic metastasis compared with HCC without intrahepatic metastasis. Less