Study on the molecular diagnosis of metastasis and recurrence and molecular targeted therapy for intractable hepato-pancreatic cancer

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According to the DNA microarray analysis using clinical samples of hepatocellular carcinoma(HCC), aurora kinase B was identified as the only independent predictor of the lethal recurrence. Preclinical tests revealed the specific inhibitor of aurora kinase B was the promising agent to treat the aggressive HCC.The distinct signature of gene expression closely related to the morphological progression in HCC. Especially, a stem cell marker EpCAM might play a critical role in the aggressiveness of confluent multinodular type of HCC.Among the alterations of transport system in the nuclear microenvironment, we focused on the importin family using microarray analysis of HCC tissues. Importin alpha1 was identified as a molecule activated functionally in HCC cells, and its significance was also validated clinicopathologically.The study showed that(i) tumor-specific hypermethylation-mediated silencing of miR-124 and miR-203 was a relatively frequent molecular event in primary HCCs and(ii) miR-124 and miR-203 exert cell growth-inhibitory effect with the downregulation of their potential targets, resulting in cell cycle arrest at the G1 S checkpoint and apoptosis, respectively.We identified the downregulation of CYP1A2 in non-cancerous liver tissue as a predictive factor for recurrence of early-stage HCC. The significance of non-cancerous CYP1A2 was confirmed by validation study using the prospective multi-center cohort. GSEA revealed that close association of CYP1A2 was implicated with the oxidative stress pathways in liver tissue.We used a fluorescence marker system for level of proteasome activity to identify pancreatic cancer cells with features of cancer stem cells(CSCs). We screened and identified a compound that is specifically toxic to the pancreatic CSCs.