ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASES EXTRACELLULAR SIGNAL-REGULATED KINASES IN HUMAN HEPATOCELLULAR-CARCINOMA

Mitogen-activated protein kinase/extracellular signal-regulated protei n kinase (MAPK/ERK) is a key molecule in intracellular signal transduc ing pathways that transport extracellular stimuli from cell surface to nuclei, MAPK/ERK has been revealed to be involved in the physiologica l proliferation of mammalian cells and also to potentiate them to tran sform, However, its role in the outgrowth of human hepatocellular carc inoma (HCC) has yet to be clarified, Therefore, in this study, we inve stigated the activation of MAPK/ERK and its associated gene expression in HCC. MAPK/ERK was activated in 15 of 26 cases of HCC we examined ( 58%), and its activity level was significantly higher in HCC than in t he adjacent non-cancerous lesions. Besides, MAPK/ERK activation in HCC was positively correlated with protein expression of transcription fa ctor c-Fos. Furthermore, in 25 of 26 cases of HCC which genomic DNA wa s available, 22 cases without genomic DNA amplification exhibited posi tive correlation, not only between protein expression of c-Fos and cyc lin D1, but also between MAPK/ERK activation and cyclin D1 expression. Concerning the relationship between MAPK/ERK activation and the clini cohistopathological features of HCC, the tumor (HCC) versus non-tumor (non-cancerous counterpart) ratio (T/N) of MAPK/ERK activity was posit ively correlated with tumor size, but neither with the stage of HCC no r the degree of differentiation of HCC, In conclusion, these findings suggest that MAPK/ERK activation in human HCC may play an important ro le in multistep hepatocarcinogenesis, especially in the progression of HCC; at least in part, through cyclin D1 up-regulation primarily indu ced by MAPK/ERK via c-Fos.