ABSTRACT
Hepatocellular carcinoma [HCC] is a common worldwide malignancy. Notch signaling pathway contributes to the genesis of diverse cancers, however, its role in HCC is unclear. Hypoxia is a common feature of HCC. Signal integration between Nothc and hypoxia may be involved in HCC. The aim of this study was to evaluate the expression of some Notch pathway genes, in addition to hypoxia inducible factor-1 alpha [HIF-l alpha] during rat hepatocellular carcinogenesis. The study aimed also, to identify any crosstalk between Notch signaling and hypoxia throughout hepatocellular oncogenesis in rats. Hepatocellular carcinogenesis was chemically induced in rats. Tissue specimens were examined histopathologically and classified into early preneoplastic group, advanced preneoplastic group, and control group. The expression of Notch-l, Dll-4, and HIF-l alpha was evaluated in tissue samples by total RNA extraction and RT-PCR. The expression of target genes were significantly increased in the diseased group. There was a significant correlation between the expression of Notch-l, Dll4, and HIF-l alpha. These results indicate that overexpression of Notch-l, Dll-4, and HIF-l alpha may be associated with the malignant transformation of hepatocytes with a possible Notch-hypoxia cross talk during hepatocellular oncogenecity
Subject(s)
Male , Animals, Laboratory , /genetics , Polymerase Chain Reaction/methods , Rats , MaleABSTRACT
Disturbance of the balance between the production of reactive oxygen species [ROS] and antioxidant defenses against them produces oxidative stress which amplifies tissue and DNA damage leading to mutagenesis, carcinogenesis and cell death. This study was undertaken to examine the role of treatment with hepanox, a commercially antioxidant, with a dose of 0.3 capsule/kg body weight/day on oxidatiuve stress and antioxidant defense methanisms on rats bearing hepatocellular carcinoma [HCC] induced by nitrosamine precurors. The activities of both blood and serum superoxide dismutase [SOD] and blood catalase, glutathione reductase [GSH-R] and glutathione peroxidase [GSH- Px] as well as the levels of glutathione [GSH], malondialdhyde [MDA] and liver tissue DNA in addition to the parameters of liver function tests [LFTs] were studied in 4 groups of 10 rats each. HCC occurs only after 7 months of nitrosamine precursors intake which was characterized by architectural and cellular damage of hepatic lubules and hepatocytes as well as increase in the levels of DNA [P<0.01]. These structrural changes were accompanied by hyperbilirubinemia, hypoalbuminemia and increase in the activities of transaminases [P<0.01]. The causative factors of these disturbances may be due to the imbalance between the activities of both GSH-R and GSHPx which result iii reduction of GSH with the increase in the duration of hepatocarcinogenic intake [P<0.01 ]. In addition, a balance between the activities of these enzymes resulted in relevation of GSH, reduction of liver DNA and blood MDA mean levels as well as normalization of LFTs in animal groups intaken hepanox and nitrosamine precursors or those intaken hepanox only as a result of controlling the process of lipid peroxidation [P<0.001]. Furthermore, the mechanisms of the protective effects of hepanox via its contents of zinc, vitamin E and sylimarin were discussed. These findings intense more light on the protective effects of hepanox, as an antioxidants containing drug, at least in part on LETs of patients with liver damage
ABSTRACT
Immunological factors are important in the pathogenesis of a wide spectrum of hepatobiliary diseases. Using flow cytometry, we determined the changes in lymphocyte subsets and natural killer cells in 123 individuals [81 patients with liver disease and 42 healthy volunteers]. The liver diseases included periportal fibrosis [PPF, 10 patients]. liver cirrhosis [LC, 31 patients], and hepatocellular carcinoma [HCC, 40 patients]. Schistosomiasis and viral hepatitis B and C were the putative etiological agents of liver diseases. Immunophenotyping by indirect immunofluorescence was conducted using monoclonal antibodies to CD3 [T-lymphocytes], CD4 [helper/inducer T-cells], CD8 [suppressor/cytotoxic T-cells] and CD 57 [natural killer cells] cell surface markers. Immunophenotyping of PPF patients showed no significant changes in all markers compared with the healthy controls. However, there was a significant decrease [P<0.01] in CD3 and CD4 T-cells, and a highly significant increase [P<0.001] in CD 57 T-cells in patients with LC or HCC. In addition, LC and HCC patients showed no significant change in CD8 T-cells compared with controls. The progression of liver diseases is associated with a dysregulation of cellular immune responses. T-lymphocytes and natural killer cells may play a role in the immunopathogenesis of LC and HCC