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  • 1
    Keywords: CELLS ; HEPATOCELLULAR-CARCINOMA ; MECHANISM ; COPY-NUMBER ; IMPORTIN-ALPHA ; HUMAN HOMOLOG ; SUSCEPTIBILITY GENE ; protein expression ; TARGET GENES ; SEGREGATION GENE CSE1
    Abstract: Proteins of the karyopherin superfamily including importins and exportins represent an essential part of the nucleocytoplasmic transport machinery. However, the functional relevance and regulation of karyopherins in hepatocellular carcinoma (HCC) is poorly understood. Here we identified cellular apoptosis susceptibility (CAS, exportin-2) and its transport substrate importin-alpha1 (imp-alpha1) among significantly up-regulated transport factor genes in HCC. Disruption of the CAS/imp-alpha1 transport cycle by RNAi in HCC cell lines resulted in decreased tumor cell growth and increased apoptosis. The apoptotic phenotype upon CAS depletion could be recapitulated by direct knockdown of the X-linked inhibitor of apoptosis (XIAP) and partially reverted by XIAP overexpression. In addition, XIAP and CAS mRNA expression levels were correlated in HCC patient samples (r=0.463; P〈0.01), supporting the in vivo relevance of our findings. Furthermore, quantitative mass spectrometry analyses of murine HCC samples (p53-/- versus p53+/+) indicated higher protein expression of CAS and imp-alpha1 in p53-/- tumors. Consistent with a role of p53 in regulating the CAS/imp-alpha1 transport cycle, we observed that both transport factors were repressed upon p53 induction in a p21-dependent manner. CONCLUSION: The CAS/imp-alpha1 transport cycle is linked to XIAP and is required to maintain tumor cell survival in HCC. Moreover, CAS and imp-alpha1 are targets of p53-mediated repression, which represents a novel aspect of p53's ability to control tumor cell growth in hepatocarcinogenesis.
    Type of Publication: Journal article published
    PubMed ID: 24799195
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  • 2
  • 3
    Keywords: CANCER ; carcinoma ; Germany ; human ; COMMON ; TOOL ; DISTINCT ; GENE ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; RAT ; MEMBER ; MEMBERS ; VARIANTS ; ACID ; antibodies ; antibody ; FORM ; IDENTIFICATION ; immunohistochemistry ; HEPATOMA ; MASS-SPECTROMETRY ; SUPERFAMILY ; CARCINOMAS ; PROTEOMIC ANALYSIS ; GEL-ELECTROPHORESIS ; ALDOSE REDUCTASE ; 2-DIMENSIONAL ELECTROPHORESIS ; REDUCTASE ; TISSUE PROTEINS ; ALDEHYDE REDUCTASE ; ALDO-KETO REDUCTASES ; LIVER-CELL-LINES ; RAT HEPATOMAS ; REDUCTASE GENE-EXPRESSION
    Abstract: The proteomic approach is a valuable tool to detect and identify proteins that are associated with cancer. In previous investigations on experimentally induced rat hepatomas, we detected aldose reductase-like protein (ARLP) as a highly significant marker protein. Our present study was intended to look for the presence of similar tumor-associated marker proteins on human hepatocellular carcinomas (HCC). We found several novel tumor-associated protein variants that represent members of the aldo-keto reductase (AKR) superfamily. Human aldose reductase-like protein-1 (hARLP-1) was the most prominent tumor-associated AKR member detected in HCC by 2-dimensional electrophoresis (2-DE) and identified by mass spectrometric fingerprinting. The enzyme was found in 4 distinct forms (hARLP-1, 36/7.4 (kd/pI); hARLP-2, 36/7.2; hARLP-3, 36/6.4; and hARLP-4, 33/7.35). In addition, a human aldose reductase-like protein (hARLP-5, 36/7.6) was identified that differed from hARLP-1 by 1 amino acid (D313N), indicating 2 allelic forms of the human aldose reductase-like gene. A novel antibody directed against common parts of the hARLPs revealed hARLP reactivity in human HCC by immunohistochemistry. Furthermore, aldose reductase (AR) was identified and characterized as a tumor-associated variant. In conclusion, in all investigated human HCCs at least one of the various types of the described tumor-associated proteins of the AKR superfamily was clearly present. Of these HCC samples, 95% were positive for hARLPs as proven by 2-DE analysis and/or by use of the antibody directed against hARLP. Thus, hARLP is a strong candidate for use as an immunohistochemical diagnostic marker of human HCC
    Type of Publication: Journal article published
    PubMed ID: 14768008
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; human ; IN-VIVO ; INHIBITION ; DEATH ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; PROTEINS ; RNA ; LINES ; MICE ; TRANSDUCTION ; NF-KAPPA-B ; COMPLEX ; COMPLEXES ; MECHANISM ; CONTRAST ; hepatocytes ; CELL-LINES ; signal transduction ; SUPPRESSION ; 5-FLUOROURACIL ; ALPHA ; hepatocellular carcinoma ; resistance ; CARCINOMA CELLS ; EFFICACY ; SIGNAL-TRANSDUCTION ; LINE ; CANCER-CELLS ; CARCINOMA-CELLS ; KAPPA-B ; RECEPTORS ; FLOW-CYTOMETRY ; cell lines ; PROTEASOME ; TRAIL ; SIGNALING COMPLEX ; HUMAN HEPATOCYTES ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; CASPASE-8 ACTIVATION ; INHIBITORS ; signaling ; RE ; INTERFERENCE ; CASPASE-8 ; MEDIATED APOPTOSIS ; TUMORICIDAL ACTIVITY ; interaction ; SIGNALING COMPLEXES ; CLINICAL-RELEVANCE ; carcinoma cell ; death receptor
    Abstract: TRAIL exhibits potent anti-tumor activity on systemic administration in mice. Because of its proven in vivo efficacy, TRAIL may serve as a novel anti-neoplastic drug. However, approximately half of the tumor cell lines tested so far are TRAIL resistant, and potential toxic side effects of certain recombinant forms of TRAIL on human hepatocytes have been described. Pretreatment with the proteasome inhibitor MG132 and PS-341 rendered TRAIL-resistant hepatocellular carcinoma (HCC) cell lines but not primary human hepatocytes sensitive for TRAIL-induced apoptosis. We investigated the different levels of possible MG132-induced interference with resistance to apoptotic signal transduction. Although proteasome inhibition efficiently suppressed nuclear factor-kappaB (NF-kappa B) activity, specific suppression of NF-kappa B by mut kappa B alpha failed to sensitize TRAIL-resistant cell lines for TRAIL-induced apoptosis. In contrast to the previously reported mechanism of sensitization by 5-fluorouracil (5-FU), cellular FLICE-inhibitory protein (cFLIP)(L) and cFLIP(S) were markedly upregulated in the TRAIL death inducing signaling complex (DISC) by proteasome inhibitor pretreatment. Compared with 5-FU pretreatment, caspase-8 was more efficiently recruited to the DISC in MG132 pretreated cells despite the presence of fewer death receptors and more cFLIP in the DISC., But downregulation of cFLIP by short interference RNA (siRNA) further sensitized the HCC cell lines. In conclusion, these results show that otherwise chemotherapy-resistant tumor cells can be sensitized for TRAIL-induced apoptosis at the DISC level in the presence of high levels of cFLIP, which suggests the existence of an additional factor that modulates the interaction of FADD and the TRAIL death receptors. Of clinical relevance, proteasome inhibitors sensitize HCC cells but not primary human hepatocytes for TRAIL-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 16037944
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; IN-VITRO ; tumor ; TUMOR-CELLS ; CELL ; COMBINATION ; Germany ; human ; IN-VIVO ; TOXICITY ; VITRO ; DEATH ; RISK ; RNA ; cell line ; LINES ; ACTIVATION ; LIGAND ; MECHANISM ; colon ; hepatocytes ; CELL-LINES ; DOWN-REGULATION ; treatment ; UP-REGULATION ; CELL-LINE ; LINE ; CANCER-CELLS ; cell lines ; pancreatic cancer ; TUMOR CELLS ; TRAIL ; MULTIPLE-MYELOMA ; HUMAN HEPATOCYTES ; APOPTOSIS-INDUCING LIGAND ; RE ; PANCREATIC-CANCER ; CAPACITY ; INTERFERENCE ; RNA INTERFERENCE ; pancreatic ; TUMOR-CELL ; CHEMOTHERAPEUTIC DRUGS ; LIGAND TRAIL ; NECROSIS ; HEPATOCELLULAR-CARCINOMA CELLS ; comparison ; BORTEZOMIB ; CAUSAL ROLE ; PROTEASOME INHIBITION
    Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a novel promising anticancer biotherapeutic. However, TRAIL-resistant tumor cells require combinatorial regimens to sensitize tumor but not normal cells for TRAIL-induced apoptosis. Here, we investigated the mechanism of the synergistic antitumor effect of bortezomib in combination with TRAIL in hepatoma, colon, and pancreatic cancer cells in comparison to the toxicity in primary human hepatocytes (PHH). TRAIL cotreatment at high but clinically relevant concentrations of bortezomib caused toxicity in PHH which potentially limits the clinical applicability of bortezomib/TRAIL cotreatment. However, at low concentrations of bortezomib TRAIL-resistant hepatoma, colon and pancreatic cancer cell lines but not PHH were efficiently sensitized for TRAIL-induced apoptosis. RNA interference and TRAIL receptor blockage experiments revealed that in bortezomib-treated hepatoma cells TRAIL-R1/TRAIL-R2 up-regulation, enhanced TRAIL DISC formation and cFLIP(L) down-regulation in addition to accumulation of Bak cooperatively sensitized for TRAIL. Bim, although accumulated upon bortezomib treatment, did not play a causal role for TRAIL sensitization in Hep3b cells. Combined treatment with bortezomib and TRAIL massively reduced the clonogenic capacity of hepatoma cells in vitro. Surviving clones could be resensitized for repeated TRAIL treatment. Conclusion: Bortezomib/TRAIL cotreatment bears the risk of severe hepatoroxicity at high but clinically relevant concentrations of bortezomib. However, within a wide therapeutic window bortezomib sensitized different cancer cells but not PHH for TRAIL-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 17326159
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  • 6
    Keywords: ACCUMULATION, ADIPOCYTES, adipophilin, ALCOHOL, ASSOCIATION, CELL, CELLS, COUNTRIES, DISORDER, DOMAI
    Abstract: Fatty change (steatosis) is the most frequent liver pathology in western countries and is caused by a broad range of disorders such as alcohol abuse and metabolic syndrome. The surface layer of lipid droplets (LDs) contains members of a protein family that share homologous sequences and domains, the so-called PAT proteins, named after their constituents, perilipin, adipophilin, and TIP47. We characterized the LD-associated proteins in normal and diseased liver connected with LD accumulation. Adipophilin and TIP47 are expressed in LDs of vitamin A-storing hepatic stellate cells and additionally in LDs of steatotic hepatocytes. Perilipin, which was thought to be characteristic for LDs of adipocytes and steroidogenic cells, becomes de novo expressed in hcpatocytes of human steatotic liver. Perilipin splice variant A was found in human steatotic hepatocytes by biochemical, molecular biological, and immunohistochemical methods. Its association with LDs is different from TIP47 and adipophilin, and depends on size and localization of the LDs, suggesting that the different PAT proteins play specific roles during maturation of LDs
    Type of Publication: Journal article published
    PubMed ID: 18393390
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  • 7
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; proliferation ; tumor ; carcinoma ; CELL ; Germany ; human ; IN-VIVO ; HEPATOCELLULAR-CARCINOMA ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; TUMORS ; ACTIVATION ; DNA ; INFECTION ; MECHANISM ; prognosis ; mechanisms ; BREAST-CANCER ; TARGET ; virus ; TRANSGENIC MICE ; COMPARATIVE GENOMIC HYBRIDIZATION ; gene expression ; NUMBER ; etiology ; RATES ; REGION ; ONCOGENE ; ALCOHOL ; OVEREXPRESSION ; gene expression profiling ; ALCOHOL-CONSUMPTION ; CONSUMPTION ; molecular ; RE ; ARRAY ; CANDIDATE GENES ; USA ; CANDIDATE ; CANCERS ; viral ; CHROMOSOME-ABERRATIONS ; ELONGATION-FACTOR EEF1A2
    Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is characterized by aggressive tumor behavior coupled with poor prognosis. Various etiologies have been linked to HCC development, most prominently chronic hepatitis B and C virus infections as well as chronic alcohol consumption. In approximately 10% of HCCs, the etiology remains cryptic; however, recent epidemiological data suggest that most of these cryptogenic HCCs develop due to nonalcoholic steatohepatitis. To identify etiology-dependent DNA copy number aberrations and genes relevant to hepatocarcinogenesis, we performed array based comparative genomic hybridization of 63 HCCs of well-defined etiology and 4 HCC cell lines followed by gene expression profiling and functional analyses of candidate genes. For a 10-megabase chromosome region on 8q24, we observed etiology-dependent copy number gains and MYC overexpression in viral and alcohol-related HCCs, resulting in up-regulation of MYC target genes. Cryptogenic HCCs showed neither 8q24 gains, nor MYC overexpression, nor target gene activation, suggesting that tumors of this etiology develop by way of a distinct MYC-independent pathomechanism. Furthermore, we detected several etiology-independent small chromosome aberrations, including amplification of MDM4 on 1q32.1 and frequent gains of EEF1A2 on 20q13.33. Both genes were overexpressed in approximately half the HCCs examined, and gene silencing reduced cell viability as well as proliferation and increased apoptosis rates in HCC cell fines. Conclusion: Our findings suggest that MDM4 and EEF1A2 act as etiology-independent oncogenes in a significant percentage of HCCs
    Type of Publication: Journal article published
    PubMed ID: 18161050
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  • 8
    Keywords: COMBINATION ; Germany ; COHORT ; DISEASE ; DISEASES ; liver ; MORTALITY ; IMPACT ; RISK-FACTORS ; ASSOCIATION ; WOMEN ; CIGARETTE-SMOKING ; MEN ; smoking ; COFFEE ; SERUM ; DETERMINANTS ; GENERAL-POPULATION ; AUSTRIAN ADULTS ; CARDIOVASCULAR-DISEASE MORTALITY
    Abstract: There is increasing evidence that serum levels of the liver enzyme gamma-glutamyltransferase (gamma-GT) are an important predictor of incidence and mortality of various diseases. Apart from alcohol consumption, body mass index and smoking have been found to be associated with serum levels, but little is known about potential interactions of these factors. The aim of this study was to assess the individual and joint impact of alcohol consumption and smoking on levels of gamma-GT, with particular attention to potential differences by sex. The study was based on data of 8465 subjects aged 50 to 74 years, obtained at baseline examination of the ESTHER study, a large population-based cohort study in Germany. Exposure-outcome relationships were assessed in women and men, adjusting for potential confounders by multiple regression. In both sexes, moderate to heavy alcohol consumption (100+ g/week) was associated with 1.7-fold increased odds of elevated gamma-GT (〉 50 IU/L) in reference to nonsmoking alcohol abstainers, whereas smoking by itself was unrelated to gamma-GT. However, when moderate to heavy alcohol consumption was present in combination with heavy smoking, the odds ratios (95% CI) increased to 2.9 (1.1-7.6) in women and to 3.8 (2.2-6.6) in men (test for interaction between alcohol consumption and smoking: P-females = 0.12, P-males = 0.0017). Conclusion: Our results support the notion of a detrimental interaction between cigarette smoking and alcohol consumption as determinants of elevated serum gamma-GT, especially in men. (HEPATOLOGY 2009;49:802-808.)
    Type of Publication: Journal article published
    PubMed ID: 19152425
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  • 9
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; human ; MICROSCOPY ; liver ; CLONING ; GENE ; microarray ; PROTEIN ; RNA ; SAMPLE ; SAMPLES ; DRUG ; TISSUE ; MESSENGER-RNA ; FAMILY ; hepatocytes ; DOWN-REGULATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; VARIANTS ; TRANSPORT ; IDENTIFICATION ; RAT-LIVER ; MEMBRANE ; AGE ; mass spectrometry ; MASS-SPECTROMETRY ; VARIABILITY ; OXALIPLATIN ; ELIMINATION ; protein expression ; FAMILIES ; VARIANT ; DETERMINANTS ; FUNCTIONAL-CHARACTERIZATION ; mRNA ; BASOLATERAL HEPATOCYTE MEMBRANE ; SUBSTRATE ; LEVEL ; GENOTYPE ; HAPLOTYPE ; HAPLOTYPES ; TECHNOLOGY ; USA ; Genetic ; Immunofluorescence microscopy ; TRANSPORTERS ; METFORMIN ACTION ; ORGANIC-CATION-TRANSPORTER-1
    Abstract: An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide single-nucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/OCT1-3 gene duster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OM mRNA and protein expression varied 113- and 83-fold, respectively, OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P 〈= 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P 〈 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P = 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin. (HEPATOLOGY 2009;50:1227-1240.)
    Type of Publication: Journal article published
    PubMed ID: 19591196
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  • 10
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; GROWTH-FACTOR ; proliferation ; CELL ; Germany ; IN-VIVO ; liver ; PROTEIN ; DIFFERENTIATION ; MICE ; ACTIVATION ; MECHANISM ; FAMILY ; T cells ; MEMBERS ; SUSCEPTIBILITY ; antibody ; DELETION ; MOUSE ; RATES ; DAMAGE ; B-CELLS ; INJURY ; FAMILIES ; development ; FULMINANT HEPATIC-FAILURE ; HUMAN HEPATOCELLULAR-CARCINOMA ; MCL-1 ; MAINTENANCE ; GROWTH-FACTORS ; OCCURS ; 33 ; ANTI-FAS ; BCL-2 PROTEINS
    Abstract: Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. It interacts with proapoptotic Bcl-2 family members, thereby inhibiting mitochondrial activation and induction of apoptosis. Mcl-1 is essential for embryonal development and the maintenance of B cells, T cells, and hematopoietic stem cells. We have recently shown that induction of Mcl-1 by growth factors rescues primary human hepatocy-tes from CD95-mediated apoptosis. This prompted us to further analyze the relevance of Mcl-1 for hepatocellular homeostasis. Therefore, we generated a hepatocyte-specific Mcl-1 knockout mouse (Mcl-1(flox/flox)-AlbCre). Deletion of Mcl-1 in hepatocytes results in liver cell damage caused by spontaneous induction of apoptosis. Livers of Mcl-1(flox/flox)-AlbCre mice are smaller compared to control littermates, due to higher apoptosis rates. As a compensatory mechanism, proliferation of hepatocytes is enhanced in the absence of Mcl-1. Importantly, hepatic pericellular fibrosis occurs in Mcl-1 negative livers in response to chronic liver damage. Furthermore, Mcl-1(flox/flox)-AlbCre mice are more susceptible to hepatocellular damage induced by agonistic anti-CD95 antibodies or concanavalin A. Conclusion: The present study provides in vivo evidence that Mcl-1 is a crucial antiapoptotic factor for the liver, contributing to hepatocellular homeostasis and protecting hepatocytes from apoptosis induction. (HEPATOLOGY 2009;49:627-636.)
    Type of Publication: Journal article published
    PubMed ID: 19127517
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