Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma

Abstract

Mitogen-activated protein kinase/extracellular signalregulated protein kinase (MAPK/ERK) is a key molecule in intracellular signal transducing pathways that transport extracellular stimuli from cell surface to nuclei. MAPK/ERK has been revealed to be involved in the physiological proliferation of mammalian cells and also to potentiate them to transform. However, its role in the outgrowth of human hepatocellular carcinoma (HCC) has yet to be clarified. Therefore, in this study, we investigated 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 the adjacent non-cancerous lesions. The mitogen-activated protein kinase/extracellular signalregulated protein kinase (MAPK/ERK) was first identified as a protein serine/threonine kinase which could be activated by a number of growth factors, cytokines, and oncogenic promoters 1,2 ; the MAPK/ERK, thereafter, was revealed to be a key molecule which converges several signal transduction pathways and transduces converged signals into nuclei, resulting in various cellular responses including proliferation and differentiation. 3,4 Numerous signals through small guanosine triphosphate (GTP)-binding protein Ras, 5 protein kinase C, 6 and other signal transducing molecules both phosphorylate and activate MAPK kinase kinases. MAPK kinase kinases, in turn, phosphorylate and activate MAPK/ERK kinase. Finally, MAPK/ERK kinase activates two isozymes of MAPK/ERK, p44 ERK1 and p42 ERK2 by phosphorylation on both threonine and tyrosine residues. In this way, signals from extracellular stimuli converge upon MAPK/ERK.Once activated, MAPK/ERK translocates into nuclei, 7-9 in which it induces transcription factors, including c-Fos and c-Jun, or activate them by phosphorylation. 10 These two transcription factors consist of activator protein-1 (AP-1) 11 and bind to AP-1 binding sites of promoter regions to induce transcription of the genes, including cyclin D1, 12 which is required for cell cycle progression in the G0/G1 phase as a G1 cyclin. 13 In addition, previous works indicate that constitutive MAPK/ERK activation results in the transformation of mammalian cells, 3,14 and that its activation is necessary for oncogenic transformation. 3 In this context, alterations in expression and activity of components of the MAPK cascade have been demonstrated in human tumors. [15][16][17] With regard to human hepatocellular carcinoma (HCC), there has been only one report on five patients where MAPK expression and activity were increased in cancerous lesions over noncancerous adjacent lesions 17 ; however, little has been revealed on the involvement of MAPK/ERK in human HCCs.Therefore, the aim of this study is to determine the activation of MAPK/ERK and expression of its associated genes, i.e., transcription factors and cell-cycle related genes, in both human HCCs and their non-cancerous counterparts, and to investigate how MAPK/ERK may be involved in the p...

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