Zekri AR, Moharram RA, Mohamed WS et al.Disease progression from chronic hepatitis C to cirrhosis and hepatocellular carcinoma is associated with repression of interferon regulatory factor-1. Eur J Gastroenterol Hepatol 22:450-456

Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
European Journal of Gastroenterology & Hepatology (Impact Factor: 2.25). 03/2010; 22(4):450-456. DOI: 10.1097/MEG.0b013e3283329d00


Background/aim: Infection with hepatitis C virus (HCV) frequently results in a persistent infection, suggesting that it has evolved efficient mechanism(s) for blocking the host cell's innate antiviral response. The immune response to virus infection results in activation or direct induction of the interferon regulatory factors (IRFs), which are a family of proteins involved in the regulation of interferon (IFN) and IFN inducible genes. IRF-3 and IRF-7 have been shown to play an essential role in virus-dependent signaling, whereas IRF-1 is critical for proper IFN-dependent gene expression. This study has been performed to show the expression profile of IRF-1, IRF-3, and IRF-7 in Egyptian patients with HCV-related liver diseases and hepatocellular carcinoma (HCC).
Materials and methods: This study included 90 patients, who were positive for HCV infection by reverse transcription PCR, divided into three groups: group I (Gr I) included 30 patients with chronic hepatitis C, group II (Gr II) included 30 patients with liver cirrhosis in addition to group III (Gr III) of 30 patients with HCC. Reverse transcription PCR analysis was performed to determine the expression profile of IRF-1, IRF-3, and IRF-7 genes extracted from the peripheral blood mononuclear cells of those patients.
Results: IRF-1expression was significantly higher (P<0.001) in patients of Gr I (86.6%) compared with those in Gr II (46.7%) and Gr III (36.7%), whereas IRF-3 expression was significantly higher (P<0.005) among patients of Gr II (73.3%) in comparison with that in Gr I (50%) and Gr III (36.7%). In contrast, although expression of IRF-7 was higher in Gr II than in the other groups, there was no statistically significant difference (P > 0.05).
Conclusion: Alterations in IRFs expression might be considered as markers associated with a higher risk of cirrhosis in patients with chronic HCV infection. Expression of IRF-1 and IRF-3 were more prevalent in patients with chronic HCV and cirrhosis, respectively, in comparison with HCC patients. Thus, IRF-1 could be nominated as one of the tumor suppressor factors and could aid in the early detection of HCC.

11 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To estimate the effect of long-term IFN treatment of human non-small-cell lung cancer cell line A-549 on their karyotype characteristics and on the clonal structure of cell population. Cytogenetic research was performed by standard methods using routine and differential staining. Cytogenetic characteristics were estimated per 1000 cells (ppm, (per thousand)). Cytogenetic analysis of IFN-modified A-549 human lung cancer cells had demonstrated far-going changes in their population structure. It was shown that long term cultivation with IFN altered the chromosome modal class of A-549 cells, induced the domination of hromosomes with certain molecular markers: the number of metaphases with der (6) t (6; 1) chromosomal rearrangement increased significantly (from 6% to 80%, p Long-term IFN effect results in alterations of cytogenetic properties of A-549 human lung cancer cells.
    Full-text · Article · Mar 2010 · Experimental oncology
  • [Show abstract] [Hide abstract]
    ABSTRACT: A second-order Møller-Plesset perturbation theory (MP2) and density functional theory (DFT) investigation of the dehalogenation reactions of thionyl halides (SOF2 and SOBr2) are reported in which water molecules (up to seven for some reaction steps) were explicitly considered in the reaction complex. The dehalogenation processes of thionyl halides were observed to be substantially catalyzed by the presence of water molecules in the reaction system. The reaction rate became faster as more water molecules became involved in the reaction complex. The dehalogenation processes can be reasonably simulated by the gas phase water cluster models and the results here indicate that water molecules can help to solvate the thionyl halide molecules so as to activate the release of a halide (F− or Br−) leaving group. Kinetic rate constants of proposed reaction pathways were estimated so as to compare with results from a previous theoretical study of the dehalogenation of SOCl2. The proposed reaction pathways show a decreasing barrier from SOF2 to SOCl2 to SOBr2 and this trend is briefly discussed.
    No preview · Article · Feb 2011 · Computational and Theoretical Chemistry
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dystrophic cutaneous calcinosis is associated with disorders as common as autoimmune diseases and cancer. To get insight into the pathogenesis of this poorly understood process, we studied the function of SAMD9, a protein of unknown function, recently shown to be deficient in a hereditary form of dystrophic calcification in the skin, known as normophosphatemic familial tumoral calcinosis (NFTC). Consistent with the fact that in NFTC severe inflammatory manifestations always precede cutaneous calcinosis, we found out that SAMD9 is tightly regulated by interferon-γ (IFN-γ). In addition, the SAMD9 promoter was also found to respond strongly to IFN-γ in a luciferase reporter assay. Of interest, we identified a critical 30-bp fragment upstream to the SAMD9 transcription initiation site responsible for driving most of the gene expression. Bioinformatic analysis suggested that SAMD9 function involves interaction with additional protein(s). Using the Ras recruitment system assay and confirmatory immunoprecipitation, we demonstrated that SAMD9 interacts with RGL2. To study the biological importance of this interaction, we assessed the effect of RNA interference-mediated downregulation of this pair of proteins in various cell lines. We found out that downregulation of any of the two protein partners caused increased expression of EGR1, a transcription factor with a known role in the regulation of tissue calcification, inflammation, and cell migration. Supporting the physiological relevance of these data, EGR1 levels were also upregulated in a fibroblast cell line derived from an NFTC patient. In conclusion, our data indicate that SAMD9, an IFN-γ-responsive protein, interacts with RGL2 to diminish the expression of EGR1, a protein of direct relevance to the pathogenesis of ectopic calcification and inflammation.
    Full-text · Article · Mar 2011 · Journal of Investigative Dermatology
Show more