Basic study for gene therapy of human liver cancer in terms of regulating signal trnasduction pathway

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The present study was aimed to elucidate the signal transduction therapy for human liver cancer. For the first experiment, we analyzed the activation of mitogen-activated protein kinase (MAPK) cascade, an intracellular signal trnasduction system involved in normal cell growth, in human liver cancerous tissues. MAPK activity was more enhanced in cancerous tissues than in adjacent non-cancerous tissues. While Raf-1 kinase, which is one of the upstream components of MAPK cascade, exhibited no significant difference in activity between cancerous and non-cancerous tissues, MEK kinase, which can activate MAPK,was increased in activity in cancerous tissues. These findings indicate that MAPK is consititutively activated in cancerous tissues in a different fashion from normal cell growth of the liver. MAPK has been previously reported to induce gene expression of transcriptional factor, followed by gene expression of the cell cycle-related genes. In human liver cancer, c-fos and c-jun expressio … More n were enhanced, accompanied by increase in cyclin D1 gene expression.Next experiment was attempted to examine which component (s) of signal transduction pathway may account for the activation of MAPK cascade in the cancerous tissues of the liver. We focus on the role of IRS-1 (insulin receptor substrate-1), a signal transducing molecule which is activated by insulin or IGF-1 and can activate MAPK cascade. The observation that IRS-1 was over-expressed and activated in liver cancers led us to construct the stable transfectant to see transformation capability of IRS-1. Stable transfectant exhibited MAPK activation, leading to tumor formation in nude mice as well as soft agar. These findings indicate that IRS-1 may contribute to liver cancer cell growth in term of activation of MAPK cascade. In conclusion, the present study suggests the possibility of signal trnasduction therapy for the prevention of cancerous cell growth of the liver by means of the inhibition of signal trnasdcution pathways. Less