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  • hepatocellular carcinoma  (5)
  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; SURVIVAL ; carcinoma ; CELL ; Germany ; human ; MODEL ; PATHWAY ; PATHWAYS ; NETWORK ; SUPPORT ; DEATH ; HEPATOCELLULAR-CARCINOMA ; liver ; GENE ; GENES ; PROTEIN ; PROTEINS ; TISSUE ; NF-KAPPA-B ; ACTIVATION ; murine ; CARCINOGENESIS ; INDUCTION ; SIGNAL ; TARGET ; MOUSE ; hepatocarcinogenesis ; hepatocellular carcinoma ; PROGRESSION ; CELL-DEATH ; CELL-LINE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; RAGE ; MOUSE MODEL ; KAPPA-B ; OXIDATIVE STRESS ; expression profiling ; inflammation ; signaling ; MOLECULAR-MECHANISMS ; cell death ; CANCER PROGRESSION ; USA ; GROWTH-CONTROL ; SUPPRESSOR-CELLS ; nuclear factor kappa B ; COEXPRESSION ; COMPENSATORY PROLIFERATION
    Abstract: The nuclear factor-kappaB (NF-kappa B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-kappa B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-kappa B-deficient and NF-kappa B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-kappa B target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-kappa B target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009;50: 1251-1262.)
    Type of Publication: Journal article published
    PubMed ID: 19670424
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; carcinoma ; CELL ; Germany ; DISEASE ; DISEASES ; HEPATOCELLULAR-CARCINOMA ; liver ; PROTEIN ; RNA ; TISSUE ; LINES ; INFECTION ; CARCINOGENESIS ; CELL-LINES ; culture ; antibodies ; antibody ; virus ; STAGE ; hepatocellular carcinoma ; immunohistochemistry ; CELL-LINE ; LINE ; MELANOMA ; HEPATOMA ; LOCALIZATION ; CARCINOMAS ; cell lines ; NUCLEAR-PORE COMPLEX ; LIVER-DISEASE ; SPECIMENS ; VIRAL-DNA ; hepatitis B and C virus ; hepatocellular carcinogenesis ; nucleoporin 88 ; NUP88
    Abstract: AIM: To investigate the expression of nucleoporin 88 (Nup88) in hepatitis B virus (HBV) and C virus (HCV)related liver diseases. METHODS: We generated a new monoclonal Nup88 antibody to investigate the Nup88 protein expression by immunohistochemistry (IHC) in 294 paraffin-embedded liver specimens comprising all stages of hepatocellular carcinogenesis. In addition, in cell culture experiments HBV-positive (HepG2.2.15 and HB611) and HBV-negative (HepG2) hepatoma cell lines were tested for the Nup88 expression by Western-immunoblotting to test data obtained by IHC. RESULTS: Specific Nup88 expression was found in chronic HCV hepatitis and unspecific chronic hepatitis, whereas no or very weak Nup88 expression was detected in normal liver. The Nup88 expression was markedly reduced or missing in mild chronic HBV infection and inversely correlated with HBcAg expression. Irrespective of the HBV- or HCV-status, increasing Nup88 expression was observed in cirrhosis and dysplastic nodules, and Nup88 was highly expressed in hepatocellular carcinomas. The intensity of Nup88 expression significantly increased during carcinogenesis (P 〈 0.0001) and correlated with dedifferentiation (P 〈 0.0001). Interestingly, Nup88 protein expression was significantly downregulated in HBV-positive HepG2.2.15 (P 〈 0.002) and HB611 (P 〈 0.001) cell lines as compared to HBV-negative HepG2 cells. CONCLUSION: Based on our immunohistochemical data, HBV and HCV are unlikely to influence the expression of Nup88 in cirrhotic and neoplastic liver tissue, but point to an interaction of HBV with the nuclear pore in chronic hepatitis. The expression of Nup88 in nonneoplastic liver tissue might reflect enhanced metabolic activity of the liver tissue. Our data strongly indicate a dichotomous role for Nup88 in nonneoplastic and neoplastic conditions of the liver. (C) 2006 The WJG Press. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17007055
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  • 3
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; SURVIVAL ; tumor ; carcinoma ; CELL ; CELL-PROLIFERATION ; Germany ; human ; INHIBITION ; VITRO ; HEPATOCELLULAR-CARCINOMA ; liver ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; RNA ; TISSUE ; LINES ; PATIENT ; ACTIVATION ; MECHANISM ; FAMILY ; REDUCTION ; TISSUES ; CONTRAST ; mechanisms ; DYNAMICS ; BINDING ; CELL-LINES ; DOWN-REGULATION ; MEMBERS ; treatment ; TARGET ; ELEMENT ; polymer ; hepatocarcinogenesis ; hepatocellular carcinoma ; MOBILITY ; CELL-LINE ; CANCER-CELLS ; MIGRATION ; MORPHOLOGY ; PHENOTYPE ; BINDING-PROTEINS ; C-MYC ; OVEREXPRESSION ; cell lines ; MITOSIS ; BINDING PROTEIN ; HUMAN BREAST-CANCER ; FAMILIES ; TUMOR-GROWTH ; PATIENT SURVIVAL ; cell proliferation ; structure ; MOLECULAR-MECHANISMS ; LEVEL ; bioavailability ; STATHMIN ; USA ; MICROTUBULE DYNAMICS ; MOTILITY ; HUMAN HEPATOCELLULAR-CARCINOMA ; DIVISION ; MALIGNANT PHENOTYPE ; MODIFIERS ; HUMAN HEPATOCARCINOGENESIS
    Abstract: Microtubule-dependent effects are partly regulated by factors that coordinate polymer dynamics such as the microtubule-destabilizing protein stathmin (oncoprotein 18). In cancer cells, increased microtubule turnover affects cell morphology and cellular processes that rely on microtubule dynamics such as mitosis and migration. However, the molecular mechanisms deregulating modifiers of microtubule activity in human hepatocarcinogenesis are poorly understood. Based on profiling data of human hepatocellular carcinoma (HCC), we identified far upstream element binding proteins (FBPs) as significantly coregulated with stathmin. Coordinated overexpression of two FBP family members (FBP-1 and FBP-2) in 〉70% of all analyzed human HCCs significantly correlated with poor patient survival. In vitro, FBP-1 predominantly induced tumor cell proliferation, while FBP-2 primarily supported migration in different HCC cell lines. Surprisingly, reduction of FBP-2 levels was associated with elevated FBP-1 expression, suggesting a regulatory interplay of FBP family members that functionally discriminate between cell division and mobility. Expression of FBP-1 correlated with stathmin expression in HCC tissues and inhibition of FBP-1 but not of FBP-2 drastically reduced stathmin at the transcript and protein levels. In contrast, further overexpression of FBP-1 did not affect stathmin bioavailability. Accordingly, analyzing nuclear and cytoplasmic areas of HCC cells revealed that reduced FBP-1 levels affected cell morphology and were associated with a less malignant phenotype. Conclusion: The coordinated activation of FBP-1 and FBP-2 represents a novel and frequent pro-tumorigenic mechanism promoting proliferation (tumor growth) and motility (dissemination) of human liver cancer cells. FBPs promote tumor-relevant functions by at least partly employing the microtubule-destabilizing factor stathmin and represent a new potential target structure for HCC treatment. (HEPATOLOGY 2009;50:1130-1139.)
    Type of Publication: Journal article published
    PubMed ID: 19585652
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; proliferation ; tumor ; carcinoma ; CELL ; Germany ; INHIBITION ; MICROSCOPY ; PATHWAY ; PATHWAYS ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; PROTEINS ; TISSUE ; TUMORS ; MICE ; ACTIVATION ; CARCINOGENESIS ; BIOLOGY ; TARGET ; hepatocellular carcinoma ; CARCINOMA CELLS ; CANCER-CELLS ; LOCALIZATION ; PHENOTYPE ; CARCINOMAS ; STRATEGIES ; TARGETS ; pathology ; DIFFERENTIAL EXPRESSION ; PATTERN ; LIGHT ; tissue microarray ; adipophilin ; FATTY-ACID SYNTHASE ; TIP47 ; STRATEGY ; PROPOSAL ; HEPATIC STEATOSIS ; lipid droplet ; PERILIPIN
    Abstract: In many human cancers, lipogenic pathways are activated; in some tumors, such as hepatocellular carcinoma, this is reflected by the presence of visible lipid droplets. Yet, the biology of steatogenesis in malignant tumors is largely unknown. We have recently shown that lipid droplet-associated proteins of the PAT-family, named after their constituents perilipin (perilipin 1), adipophilin (perilipin 2), and TIP47 (perilipin 3) are differentially expressed in hepatic steatogenesis. We have comprehensively investigated PAT-expression in neoplastic steatogenesis as well as in respective normal tissues with immunohistology and electron microscopy as well as protein biochemical and molecular biological methods. By staining for PAT-proteins, we found lipid droplet accumulation to be a frequent phenomenon of carcinoma cells. Although adipophilin and TIP47 stained almost ubiquitously the rim of lipid droplets in various tumor types, especially those with clear cell phenotype, perilipin was restricted to lipid droplets of hepatocellular adenoma and carcinoma, sebaceous adenoma and carcinoma, and lipomatous tumors. In hepatocellular carcinoma, perilipin, adipophilin, and TIP47 were coexpressed, and showed regional heterogeneity with a predominantly mutually exclusive localization pattern. In step-wise carcinogenesis, adipophilin expression correlated with the proliferation rate and was upregulated during early tumorigenesis, whereas perilipin was often lost during hepatocarcinogenesis. In conclusion, expression analysis of PAT-proteins showed that by far more carcinomas contain (PAT-positive) lipid droplets than expected by conventional light microscopy. PAT-proteins, such as perilipin, are differentially expressed in different tumor types and thus may support diagnostic considerations. Because inhibition of lipogenesis has been shown to exert antineoplastic effects, PAT-proteins may represent targets for interventive strategies. Modern Pathology (2010) 23, 480-492; doi: 10.1038/modpathol.2009.191; published online 15 January 2010
    Type of Publication: Journal article published
    PubMed ID: 20081801
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  • 5
    Keywords: IN-VITRO ; PRIMARY LIVER-CANCER ; GENES ; TARGET ; hepatocellular carcinoma ; ABERRATIONS ; REGION ; ABNORMALITIES ; CHROMOSOMAL INSTABILITY ; HUMAN HEPATOCELLULAR-CARCINOMA ; B VIRUS-DNA ; HBV ; oncomodel
    Abstract: Classical comparative genomic hybridization (CGH) has been used to identify recurrent genomic alterations in human HCC. As hepatocarcinogenesis is considered as a stepwise process, we applied oncogenetic tree modeling on all available classical CGH data to determine occurrence of genetic alterations over time. Nine losses (1p, 4q, 6q, 8p, 9p, 13q, 16p, 16q and 17p) and ten gains (1q, 5p, 6p, 7p, 7q, 8q, 17q, 20p, 20q and Xq) of genomic information were used to build the oncogenetic tree model. Whereas gains of 1q and 8q together with losses of 8p formed a cluster that represents early etiology-independent alterations, the associations of gains at 6q and 17q as well as losses of 6p and 9p were observed during tumor progression. HBV-induced HCCs had significantly more chromosomal aberrations compared to HBV-negative tumors. Losses of 1p, 4q and 13q were associated with HBV-induced HCCs, whereas virus-negative HCCs showed an association of gains at 5p, 7, 20q and Xq. Using five aberrations that were significantly associated with tumor dedifferentiation a robust progression model of stepwise human hepatocarcinogensis (gain 1q -〉 gain 8q -〉 loss 4q -〉 loss 16q -〉 loss 13q) was developed. In silico analysis revealed that protumorigenic candidate genes have been identified for each recurrently altered hotspot. Thus, oncogenic candidate genes that are coded on chromosome arms 1q and 8q are promising targets for the prevention of malignant transformation and the development of biomarkers for the early diagnosis of human HCC that may significantly improve the treatment options and thus prognosis of HCC patients
    Type of Publication: Journal article published
    PubMed ID: 21400513
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