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Berlin Brandenburg

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  • 1
    Language: English
    In: 11/2012, Vol.30(5), pp.1133-1137
    Description: The repellent factor family of Slit molecules has been described as having a repulsive function in the developing nervous system on growing axons expressing the Roundabout (Robo) receptors. Recent studies determined the effects of Slit molecules on the migratory and invasive potential of several types of tumor cells but also on synovial fibroblasts (SFs) derived from rheumatoid arthritis (RA) patients. To optimize a potential therapeutic application we aimed at generatingfragments of Slit3 showing the same functional ability as the full-length molecule but having the advantage of a smaller size. Recombinant Slit3 proteins were expressed and analyzed by western blotting. Their activity was defined by functional assays such as migration assays with RASF and melanoma cells. Recombinant Slit3 containing only leucine rich repeat domain 2 (D2), the domain important for Robo binding and the minimal functional unit D2 dNC were both able to inhibit migration of RASFs as effectively as Slit3 with all 4 repeats. Collectively, our data showed that the ability of Slit3 to reduce the migratory activity of synovial cells from patients with RA and melanoma cells can be mimicked by small protein fragments derived from Slit3. Slit3 fragments may be helpful in therapeutic attempts; however, further studies are necessary in order to elucidate their activity in vivo .
    Keywords: Repellent Factor ; Slit ; Roundabout ; Migration ; Proliferation ; Rheumatoid Arthritis ; Melanoma ; Recombinant Proteins
    ISSN: 1107-3756
    E-ISSN: 1791-244X
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  • 2
    In: Oncogene, 2012, Vol.32(7), p.837
    ISSN: 0950-9232
    E-ISSN: 1476-5594
    Source: Nature Publishing Group
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  • 3
    Language: English
    In: International Journal of Molecular Medicine, November 2011, Vol.28(5), pp.721-726
    Description: The repellent factor family of Slit molecules has been described to have repulsive function in the developing nervous system on growing axons expressing the Robo receptors. Alterations of the Slit/Robo system have been observed in various pathological conditions and in cancer. However, until today no detailed studies on Slit function on melanoma migration are available. Therefore, we analysed the mRNA expression in melanoma cells and found induction of Robo3 expression compared to normal melanocytes. Functional assays performed with melanoma cells revealed that treatment with Slit3 led to strong inhibition of migration. Interestingly, we observed down-regulation of AP-1 activity and target gene expression after Slit3 treatment contributing to the negative regulation of migration. Taken together, our data showed that Slit3 reduces the migratory activity of melanoma cells, potentially by repulsion of the cells in analogy to the neuronal system. Further studies will be necessary to prove Slit activity in vivo, but due to its function, Slit3 activity may be helpful in the treatment of melanoma.
    Keywords: Melanoma -- Metabolism ; Membrane Proteins -- Pharmacology ; Nerve Tissue Proteins -- Metabolism ; Receptors, Immunologic -- Metabolism;
    ISSN: 1107-3756
    E-ISSN: 1791244X
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  • 4
    Language: English
    In: International Journal of Oncology, July 2011, Vol.39(1), pp.235-243
    Description: The Wnt/β-catenin pathway is involved in differentiation events during embryonic development and is further described as a pathway often participating in tumor formation when aberrantly activated. Molecular studies concentrating on colorectal cancer revealed mutations of apc, ctnnbi, btrc and tcf-4 genes which mimic Wnt stimulation. However, such mutations are rarely found during melanoma development. Therefore, we analyzed the β-catenin activity in this type of skin cancer. Interestingly, localization of β-catenin protein was basically cytoplasmic in melanomas in vivo, which was in clear contrast to findings in colon carcinoma. Congruently, the transcriptional activity of β-catenin regulating expression of β-catenin target genes was not observed in several melanoma cell lines. Further, neither LiCl nor Wnt agonist treatment led to significant activation of β-catenin signaling. This lack in functionality seems to depend on phosphorylation at threonine 41 and serine 45 of β-catenin observed in several melanoma cell lines. However, this specific endogenous phosphorylation pattern led to upregulation of other signaling pathways resulting e.g. in induction of N-cadherin expression. In summary, this study suggests a cell type-specific regulation of β-catenin function. This alternative β-catenin signaling pathway should be considered when thinking about targeting β-catenin in melanoma treatment.
    Keywords: Signal Transduction ; Melanoma -- Physiopathology ; Beta Catenin -- Metabolism;
    ISSN: 1019-6439
    E-ISSN: 17912423
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  • 5
    In: British Journal of Cancer, 2014
    Keywords: Argonaute Proteins -- Deficiency ; Melanoma -- Metabolism ; Micrornas -- Genetics;
    ISSN: 0007-0920
    E-ISSN: 15321827
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  • 6
    Language: English
    In: PLoS ONE, 2011, Vol.6(7), p.e22908
    Description: Patent ductus arteriosus (PDA) is one of the most common forms of congenital heart disease. Mutations in transcription factor TFAP2B cause Char syndrome, a human disorder characterized by PDA, facial dysmorphysm and hand anomalies. Animal research data are needed to understand the mechanisms. The aim of our study was to elucidate the pathogenesis of Char syndrome at the molecular level. ; Gene expression of during mouse development was studied, and newborns of Tfap2b-deficient mice were examined to identify phenotypes. Gel shift assays had been carried out to search for Tfap2 downstream genes. Promoters of candidate genes were cloned into a reporter construct and used to demonstrate their regulation by Tfap2b in cell transfection. In situ hybridizations showed that the murine transcription factor was expressed during the entire development of mouse ductus arteriosus. Histological examination of ductus arteriosus from knockout mice 6 hours after birth revealed that they were not closed. Consequently, the lungs of mice demonstrated progressive congestion of the pulmonary capillaries, which was postulated to result secondarily from PDA. In addition, was expressed in the limb buds, particularly in the posterior limb field during development. Lack of resulted in bilateral postaxial accessory digits. Further study indicated that expressions of bone morphogenetic protein () genes, which are reported to be involved in the limb patterning and ductal development, were altered in limb buds of Tfap2b-deficient embryos, due to direct control of and promoter activity by Tfap2b. ; Tfap2b plays important roles in the development of mouse ductus arteriosus and limb patterning. Loss of Tfap2b results in altered Bmp expression that may cause the heart-limb defects observed in mouse mutants and Char syndrome patients. The Tfap2b knockout mouse may add to the very limited available animal models of PDA.
    Keywords: Research Article ; Biology ; Medicine ; Biotechnology
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: International Journal of Cancer, 01 September 2011, Vol.129(5), pp.1064-1074
    Description: Resulting from a screening for microRNAs differentially regulated in melanocytes and melanoma cells, we found expression of miR‐196a to be significantly down‐regulated in malignant melanoma cell lines and tissue samples. As it was stated before that miR‐196a might negatively regulate expression of the transcription factor HOX‐C8, we analyzed HOX‐C8 levels in NHEMs and melanoma cells and found a strong up‐regulation of HOX‐C8 expression in malignant melanoma cell lines and tissue samples compared with melanocytes. Several HOX‐C8 target genes are known to be involved in processes such as oncogenesis, cell adhesion, proliferation and apoptosis. We, therefore, aimed to further investigate a potential “miR‐196a → HOX‐C8 → HOX‐C8 target gene” relationship. Stable transfection with an miR‐196a expression plasmid led to strong down‐regulation of HOX‐C8 expression in melanoma cells. Luciferase assays using reporter plasmids containing different fragments of the HOX‐C8 3′UTR confirmed direct interactions of miR‐196a with the HOX‐C8 mRNA. Focusing on target genes of HOX‐C8, which might play an important role in melanomagenesis, we identified three genes (, and ) that are up‐ or down‐regulated, respectively, by altered HOX‐C8 expression in miR‐196a expressing cell clones and are thus indirectly regulated by this microRNA. As those target genes are closely related to important cellular mechanisms such as cell adhesion, cytoskeleton remodeling, tumor formation and invasive behavior of tumor cells, altered miR‐196a expression exerts strong effects contributing to tumor cell transformation and formation and progression of malignant melanoma. This fact is underlined by a strongly reduced invasive behavior of melanoma cells re‐expressing miR‐196a .
    Keywords: Malignant Melanoma ; Mirna ; Hox Genes ; Cadherin‐11 ; Calponin‐1 ; Osteopontin ; Hugl‐1
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 8
    Language: English
    In: Oncogene, 14 February 2013, Vol.32(7), pp.837-48
    Description: Bone morphogenetic proteins (BMPs) are known to play an important role in melanoma development and progression. However, the downstream targets of BMPs have not been investigated thus far. Therefore, we treated melanoma cell lines with the Smad-specific BMP inhibitor Dorsomorphin and performed a cDNA microarray. We identified death inducer-obliterator 1 (Dido1) as a BMP-specific Smad-regulated target gene, which was confirmed by qRT-PCR, immunofluorescence staining and electrophoretic mobility shift assay experiments. An analysis of Dido1 expression revealed an upregulation of Dido1 levels in melanoma cell lines and tissues compared with normal melanocytes. Colony-formation assays showed that siDido1-transfected cells formed significantly smaller colonies when grown in soft agar compared with control cells. In addition, fluorescence-activated cell sorting and western blot experiments revealed that transfection of melanoma cells with Dido1 small interfering RNAs led to an upregulation of apoptosis. Furthermore, cell migratory and invasive potentials were strongly reduced in siDido1-transfected cells compared with control cells. Finally, we demonstrated that Dido1 induces the expression of Integrin αV, thereby promoting the attachment, migration, invasion and apoptosis resistance of melanoma cells.
    Keywords: Bone Morphogenetic Proteins -- Pharmacology ; DNA-Binding Proteins -- Physiology ; Gene Expression Regulation, Neoplastic -- Drug Effects ; Melanoma -- Genetics ; Skin Neoplasms -- Genetics
    ISSN: 09509232
    E-ISSN: 1476-5594
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  • 9
    Language: English
    In: Biochemical and Biophysical Research Communications, 28 September 2012, Vol.426(3), pp.404-408
    Description: ► The expression of the atypical cadherin FAT1 is increased in chronic liver disease. ► FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). ► Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. ► FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. ► FAT1 is a new therapeutic target for prevention and treatment of hepatic fibrosis. Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these cells by siRNA. We newly found that FAT1 suppression in activated HSCs caused a downregulation of NFκB activity. This transcription factor is critical for apoptosis resistance of HSCs, and consequently, we detected a higher apoptosis rate in FAT1 suppressed HSCs compared to control cells. Our findings suggest FAT1 as new therapeutic target for the prevention and treatment of hepatic fibrosis in chronic liver disease.
    Keywords: Fat1 ; Cadherin ; Hepatic Fibrosis ; Apoptosis ; Hepatic Stellate Cells ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 10
    In: British Journal of Cancer, 2013, Vol.109(12), p.3116
    Description: BACKGROUND: Processing of microRNAs (miRNAs) is a highly controlled process. Deregulation of miRNA expression was observed in several types of cancer but changes in the miRNA-processing enzymes have not been analysed until today. In this study, we analysed Argonaute2 (AGO2, EIF2C2), as one main factor of the miRNA processing ensemble, in the context of cancer development, especially in melanoma.METHODS: We determined the AGO2 expression level in melanoma, as well as in other cancers, with biochemical approaches (qRT-PCR, western blot and immunofluorescence studies) and analysed the cell behaviour in migration assays.RESULTS: Specifically in melanoma, we revealed a strong reduction of AGO2 expression compared with primary melanocytes. The reduction of AGO2 expression was only found on protein level, whereas the mRNA level stayed unchanged hinting to post-transcriptional regulation. We could show that re-expression of AGO2 in melanoma leads to a strong improvement of regulatory effects due to increased functionality of small-interfering RNAs and short hairpin RNAs.CONCLUSION: We identified melanoma-specific downregulation of AGO2 and corresponding reduced RNAi efficiency. These findings will help to understand the molecular basis of malignant melanoma and can potentially lead to an improvement of therapeutic strategies.
    Keywords: Medicine;
    ISSN: 0007-0920
    E-ISSN: 15321827
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