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  • 1
    Keywords: EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; human ; INFORMATION ; HEPATOCELLULAR-CARCINOMA ; HISTORY ; GENE ; GENES ; HYBRIDIZATION ; DIFFERENTIATION ; TUMORS ; RESOLUTION ; DNA ; MECHANISM ; mechanisms ; ADENOMAS ; hepatocellular carcinoma ; PROGRESSION ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; NUMBER ; CHROMOSOMAL-ABERRATIONS ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; TUMOR-SUPPRESSOR GENE ; REGION ; INSTABILITY ; REGIONS ; ONCOGENE ; TRANSFORMATION ; ORAL-CONTRACEPTIVES ; CARCINOMAS ; IMBALANCES ; CLUSTER ; MOLECULAR-MECHANISM ; TUMOR-SUPPRESSOR ; INCREASE ; CLUSTER-ANALYSIS ; CHROMOSOMAL INSTABILITY ; CHIP ; tumor suppressor gene ; cluster analysis ; LOSSES ; GLYCOGEN-STORAGE-DISEASE ; genomic ; HUMAN HEPATOCELLULAR-CARCINOMA ; ARRAY CGH ; CHROMOSOMAL-ABNORMALITIES ; TUMOR-SUPPRESSOR GENES ; ARRAY-CGH ; LIVER-CELL ADENOMAS
    Abstract: Background & Alms: To gain more information about the molecular mechanisms leading to dedifferentiation of hepatocellular adenoma (HCA) and hepatocellular carcinoma (HCC), high-resolution array-based comparative genomic hybridization (array-CGH) was performed on 24 cases of HCC and 10 cases of HCA. Methods: DNA chips containing 6251 individual bacterial artificial chromosome/plasmid artificial chromosome clones were used. They allowed for a genome-wide resolution of 1 Mb and an even higher resolution of up to 100 kb for chromosome regions recurrently involved in human tumors and for regions containing known tumor-suppressor genes and oncogenes. Results: Copy number changes on the genomic scale were found by array-based comparative genomic hybridization in all cases. In HCC, gains of chromosomal regions 1q (91.6%), and 8q (58.3%), and losses of 8p (54%) were found most frequently. Hierarchic cluster analysis branched all HCA from HCC. However, in 2 adenomas with a known history of glycogenosis type I and adenomatosis hepatis gains of 1q were found, too. The critically gained region was narrowed down to bands 1q22-23. Although no significant differences in the mean number of chromosomal aberrations were seen between adenomas and well-differentiated carcinomas (2.7 vs 4.6), a significant increase accompanied the dedifferentiation of HCC (14.1 in HCC-G2 and 16.3 in HCC-G2/3; P 〈 .02). Dedifferentiation of HCC also was correlated closely to losses of 4q and 13q (P 〈 .001 and 〈 .005, respectively). Conclusions: The increased chromosomal instability during dedifferentiation of HCC leads to an accumulation of structural chromosomal aberrations and losses and gains of defined chromosome regions
    Type of Publication: Journal article published
    PubMed ID: 16979954
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  • 2
    Abstract: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma. Interferons (IFNs) are crucial for HCV clearance and a sustained virological response (SVR), but a significant proportion of patients do not respond to IFNalpha. The underlying mechanisms of an insufficient IFN response remain largely unknown. In this study, we found that patients responding to IFNalpha with viral clearance had significantly higher serum levels of TNF-related apoptosis inducing ligand (TRAIL), compared with patients who failed to control HCV. In addition, upon direct IFNalpha exposure, peripheral blood mononuclear cells (PBMCs) from patients with SVR upregulated TRAIL, as well as IFN-gamma and the chemokines CXCL9 and CXCL10, much more strongly than cells from patients with antiviral treatment failure. As a possible mechanism of the stronger IFNalpha-induced cytokine response, we identified higher levels of expression and phosphorylation of the transcription factor STAT1 in PBMCs from patients with SVR. Increased TRAIL expression additionally involved the NF-kappaB and JNK signaling pathways. Thus, SVR in chronic HCV infection is associated with a strong IFNalpha-induced cytokine response, which might allow for the early prediction of treatment efficacy in HCV infection.
    Type of Publication: Journal article published
    PubMed ID: 26503984
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  • 3
    Keywords: LUNG-CANCER ; HEPATOCELLULAR-CARCINOMA ; GENE-EXPRESSION ; GENOME ; IDENTIFICATION ; C-MYC ; POOR-PROGNOSIS ; INCREASED EXPRESSION ; CODING REGION ; CRD-BP
    Abstract: Selected long non-coding RNAs (lncRNAs) have been shown to play important roles in carcinogenesis. Although the cellular functions of these transcripts can be diverse, many lncRNAs regulate gene expression. In contrast, factors that control the expression of lncRNAs remain largely unknown. Here, we investigated the impact of RNA binding proteins on the expression of the liver cancer-associated lncRNA HULC (Highly Up-regulated in Liver Cancer). First, we validated the strong up-regulation of HULC in human hepatocellular carcinoma. To elucidate post-transcriptional regulatory mechanisms governing HULC expression, we applied an RNA affinity purification approach to identify specific protein interaction partners and potential regulators. This method identified the family of IGF2BPs (IGF2 mRNA-binding proteins) as specific binding partners of HULC. Depletion of IGF2BP1, also known as IMP1, but not of IGF2BP2 or -3, led to an increased HULC half-life and higher steady-state expression levels, indicating a post-transcriptional regulatory mechanism. Importantly, HULC represents the first IGF2BP substrate that is destabilized. To elucidate the mechanism by which IGF2BP1 destabilizes HULC, the CNOT1 protein was identified as a novel interaction partner of IGF2BP1. CNOT1 is the scaffold of the human CCR4-NOT deadenylase complex, a major component of the cytoplasmic RNA decay machinery. Indeed, depletion of CNOT1 increased HULC half-life and expression. Thus, IGF2BP1 acts as an adaptor protein that recruits the CCR4-NOT complex and thereby initiates the degradation of the lncRNA HULC. Conclusion: Our findings provide important insights into the regulation of lncRNA expression and identify a novel function for IGF2BP1 in RNA metabolism.
    Type of Publication: Journal article published
    PubMed ID: 23728852
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  • 4
    Keywords: IN-VITRO ; LUNG-CANCER ; GENES ; GENOME ; PROGRESSION ; C-MYC ; POOR-PROGNOSIS ; INCREASED EXPRESSION ; CRD-BP ; LIVER-CANCER CELLS
    Abstract: Hepatocarcinogenesis is a stepwise process. It involves several genetic and epigenetic alterations, e.g., loss of tumor suppressor gene expression (TP53, PTEN, RB) as well as activation of oncogenes (c-MYC, MET, BRAF, RAS). However, the role of RNA-binding proteins (RBPs), which regulate tumor suppressor and oncogene expression at the posttranscriptional level, are not well understood in hepatocellular carcinoma (HCC). Here we analyzed RBPs induced in human liver cancer, revealing 116 RBPs with a significant and more than 2-fold higher expression in HCC compared to normal liver tissue. We focused our subsequent analyses on the Insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 1 (IGF2BP1) representing the most strongly up-regulated RBP in HCC in our cohort. Depletion of IGF2BP1 from multiple liver cancer cell lines inhibits proliferation and induces apoptosis in vitro. Accordingly, murine xenograft assays after stable depletion of IGF2BP1 reveal that tumor growth, but not tumor initiation, strongly depends on IGF2BP1 in vivo. At the molecular level, IGF2BP1 binds to and stabilizes the c-MYC and MKI67 mRNAs and increases c-Myc and Ki-67 protein expression, two potent regulators of cell proliferation and apoptosis. These substrates likely mediate the impact of IGF2BP1 in human liver cancer, but certainly additional target genes contribute to its function. Conclusion: The RNA-binding protein IGF2BP1 is an important protumorigenic factor in liver carcinogenesis. Hence, therapeutic targeting of IGF2BP1 may offer options for intervention in human HCC.
    Type of Publication: Journal article published
    PubMed ID: 24395596
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