Liver cirrhosis is the irreversible end result of fibrous scarring and hepatocellular regeneration, characterized by diffuse disorganization of the normal hepatic structure of regenerative nodules and fibrotic tissue. It is associated with prominent morbidity and mortality, and is induced by many factors, including chronic hepatitis virus infections, alcohol drinking and drug abuse. Hepatocyte growth factor (HGF), originally identified and cloned as a potent mitogen for hepatocytes, shows mitogenic, motogenic and morphogenic activities for a wide variety of cells. Moreover, HGF plays an essential part in the development and regeneration of the liver, and shows anti-apoptotic activity in hepatocytes. In a rat model of lethal liver cirrhosis produced by dimethylnitrosamine administrations, repeated transfections of the human HGF gene into skeletal muscles induced a high plasma level of human as well as enodogenous rat HGF, and tyrosine phosphorylation of the c-Met/HGF receptor. Transduction with the HGF gene also suppressed the increase of transforming growth factor-beta1 (TGF-beta1), which plays an essential part in the progression of liver cirrhosis, inhibited fibrogenesis and hepatocyte apoptosis, and produced the complete resolution of fibrosis in the cirrhotic liver, thereby improving the survival rate of rats with this severe illness. Thus, HGF gene therapy may be potentially useful for the treatment of patients with liver cirrhosis, which is otherwise fatal and untreatable by conventional therapy.

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...

and several other cell types, including endothelial cells and The c-met proto-oncogene encodes the tyrosine kinase melanocytes. 4,5 receptor for hepatocyte growth factor (HGF), a potent It has been reported that the expression of c-met is enmitogen and motogen for epithelial cells. Because of its hanced in thyroid, 6 gastric, 7 colorectal, 8 and prostatic canprofound effects on cell growth and motility, HGF may cers, 9 which suggests that an altered expression of c-met may be important in the development of cancer metastases be involved in cancer development. With respect to HCC, in hepatocellular carcinoma (HCC). In this study, we exseveral reports have been written on c-met expression. Prat amined HGF concentration and expression of the c-metet al. 10 reported the expression of c-met protein in 11 of 14 proto-oncogene product (c-met) in 62 patients with HCC HCCs using immunofluorescence, and Boix et al. 11 reported to determine the relationship between the level of exthat overexpression of c-met messenger RNA (mRNA) was pression and clinicopathological features, and patient detected in 8 of 18 HCCs. Suzuki et al. showed that c-met outcome following hepatectomy. Western blotting was protein was correlated with differentiation of HCC cells. 12used to examine the c-met expression, and HGF concenHowever, the relationship between c-met expression and tutration in tumors was measured using an enzyme-linked mor development, metastases, and patient outcome has not immunosorbent assay. c-met was found to be overexbeen clarified. pressed in HCC compared with nontumorous liver tissueIn this study, we examined c-met expression and HGF con-(P õ .01), and correlated with an increased incidence of centration in HCC and in nontumorous hepatic tissue, and intrahepatic metastases (P Å Hepatocyte growth factor (HGF) is a pleiotropic polypep-resection. Chronic liver disease was noted as follows: cirrhosis, 51 tide growth factor with a number of biological activities, in-(82.3%); chronic hepatitis, fibrosis, or both, 6 (9.6%). Twelve patients (19%) indicated the presence of hepatitis B surface antigen, and 23 cluding mitogenic, motogenic, and/or morphogenic proper-(37%) showed anti-hepatitis B surface antibody and/or anti-hepatitis ties, in a variety of epithelial tissues. Because HGF is a potent core antibody by enzyme-linked immunosorbent assay. Fifty-five of mitogen in hepatocytes, its involvement in the growth and 62 patients were tested with a second-generation hepatitis C virus development of metastases in hepatocellular carcinoma antibody (Ortho Diagnostics, Raritan, NJ), and 70.9% revealed the (HCC) is suspected. Recently, purified HGF has been shown presence of hepatitis C virus. A tumor sample and nontumorous to stimulate invasive characteristics in various cancer cells tissue were obtained immediately after the liver resection and were in vitro, 1,2 therefore, it is possible that HGF plays an im-snap-frozen in liquid nitrogen and stored at 080ЊC. Histological secportant role in the establishment of intrahepatic m...

mal and malignant epithelial cells and several other cell The c-met proto-oncogene encodes the tyrosine kinase types, including endothelial cells and melanocytes. 4,5 receptor for hepatocyte growth factor (HGF), a potent It has been reported that the expression of c-Met is enmitogen and motogen for epithelial cells. Because of its hanced in thyroid, 6 gastric, 7 colorectal, 8 and prostatic canprofound effects on cell growth and motility, HGF may cers, 9 which suggests that an altered expression of c-Met may be important in the development of cancer metastases be involved in cancer development. With respect to HCC, few in hepatocellular carcinoma (HCC). In this study, we exreports have been written on c-met expression. Prat et al. 10 amined HGF concentration and expression of the c-met have reported the expression of c-met protein in 11 of 14 proto-oncogene product (c-Met) in 62 patients with HCC HCCs using immunofluorescence, and Boix et al. 11 have reto determine the relationship between the level of exported that overexpression of c-met messenger RNA (mRNA) pression and clinicopathological features, and patient was detected in 8 of 18 HCCs. Suzuki et al. have shown outcome following hepatectomy. Western blotting was that c-met protein was correlated with differentiation of HCC used to examine the c-Met expression, and HGF concencells. 12 However, the relationship between c-Met expression tration in tumors was measured using an enzyme-linked and tumor development, metastases, and patient outcome immunosorbent assay. c-Met was found to be overexhas not been clarified. pressed in HCC compared with nontumorous liver tissueIn this study, we examined c-Met expression and HGF con-(P õ .01), and correlated with an increased incidence of centration in HCC and in nontumorous hepatic tissue, and intrahepatic metastases (P Å Hepatocyte growth factor (HGF) is a pleiotropic polypep-resection. Chronic liver disease was noted as follows: cirrhosis, 51 tide growth factor with a number of biological activities, in-(82.3%); chronic hepatitis, fibrosis, or both, 6 (9.6%). Twelve patients (19%) indicated the presence of hepatitis B surface antigen, and 23 cluding mitogenic, motogenic, and/or morphogenic proper-(37%) showed anti-hepatitis B surface antibody and/or anti-hepatitis ties, in a variety of epithelial tissues. Because HGF is a potent core antibody by enzyme-linked immunosorbent assay. Fifty-five of mitogen in hepatocytes, its involvement in the growth and 62 patients were tested with a second-generation hepatitis C virus development of metastases in hepatocellular carcinoma antibody (Ortho Diagnostics, Raritan, NJ), and 70.9% revealed the (HCC) is suspected. Recently, purified HGF has been shown presence of hepatitis C virus. A tumor sample and nontumorous to stimulate invasive characteristics in various cancer cells tissue were obtained immediately after the liver resection and were in vitro, 1,2 therefore, it is possible that HGF plays an im-snap-frozen in liquid nitrogen and stored at 080ЊC. Histological secportant ro...

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