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Berlin Brandenburg

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  • 1
    Language: English
    In: Cancer research, 15 January 2016, Vol.76(2), pp.197-205
    Description: Cancer stem-like cells (CSC) have been proposed to promote cancer progression by initiating tumor growth at distant sites, suggesting that stem-like cell features can support metastatic efficiency. Here, we demonstrate that oncogenic DNp73, a dominant-negative variant of the tumor-suppressor p73, confers cancer cells with enhanced stem-like properties. DNp73 overexpression in noninvasive melanoma and lung cancer cells increased anchorage-independent growth and elevated the expression of the pluripotency factors CD133, Nanog, and Oct4. Conversely, DNp73 depletion in metastatic cells downregulated stemness genes, attenuated sphere formation and reduced the tumor-initiating capability of spheroids in tumor xenograft models. Mechanistic investigations indicated that DNp73 acted by attenuating expression of miR-885-5p, a direct regulator of the IGF1 receptor (IGF1R) responsible for stemness marker expression. Modulating this pathway was sufficient to enhance chemosensitivity, overcoming DNp73-mediated drug resistance. Clinically, we established a correlation between low p73 function and high IGF1R/CD133/Nanog/Oct4 levels in melanoma specimens that associated with reduced patient survival. Our work shows how DNp73 promotes cancer stem-like features and provides a mechanistic rationale to target the DNp73-IGF1R cascade as a therapeutic strategy to eradicate CSC.
    Keywords: DNA-Binding Proteins -- Genetics ; Micrornas -- Genetics ; Neoplastic Stem Cells -- Pathology ; Nuclear Proteins -- Genetics ; Tumor Suppressor Proteins -- Genetics
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 2
    Language: English
    In: PLoS ONE, 2011, Vol.6(9), p.e25378
    Description: Hepatitis E virus (HEV) is a non-enveloped plus-strand RNA virus that causes acute hepatitis. The capsid protein open reading frame 2 (ORF2) is known to induce endoplasmic reticulum stress in ORF2 expressing cells. ; In this study we found that HEV ORF2 activates the expression of the pro-apoptotic gene C/EBP homologous protein (CHOP). ORF2 stimulates the CHOP promoter mainly through AARE (amino acid response elements) and to a minor extent the ERSE (endoplasmic reticulum stress response elements). Activating transcription factor 4 (ATF4) protein binds and activates the AARE regulatory sites of the CHOP promoter. ORF2 expression also leads to increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) that in turn initiates the translation of ATF4 mRNA. The pro-apoptotic gene CHOP is an important trigger to initiate endoplasmic reticulum stress induced apoptosis. However, the activation of CHOP by ORF2 in this study did not induce apoptosis, nor did BCL2-associated X protein (Bax) translocate to mitochondria. Microarray analysis revealed an ORF2 specific increased expression of chaperones Hsp72, Hsp70B', and co-chaperone Hsp40. Co-immunoprecipitation (Co-IP) and molecular docking analysis suggests that HEV ORF2 interacts with Hsp72. In addition, Hsp72 shows nuclear accumulation in ORF2 expressing cells. ; These data provide new insight into simultaneously occurring counter-acting effects of HEV ORF2 that may be part of a strategy to prevent host suicide before completion of the viral replication cycle.
    Keywords: Research Article ; Biology ; Genetics And Genomics ; Virology ; Molecular Biology ; Computational Biology
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Cancer Research, 08/01/2015, Vol.75(15 Supplement), pp.4099-4099
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    Language: English
    In: Cancer Research, 04/01/2016, Vol.76(7 Supplement), pp.B27-B27
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 5
    Language: English
    In: Cancer Research, 04/01/2016, Vol.76(7 Supplement), pp.B26-B26
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 6
    Language: English
    In: Oncotarget, 15 January 2014, Vol.5(1), pp.3-4
    Keywords: Gene Expression Regulation, Neoplastic ; Cytoskeletal Proteins -- Metabolism ; DNA-Binding Proteins -- Physiology ; Melanoma -- Metabolism ; Nuclear Proteins -- Physiology ; Receptor, IGF Type 1 -- Metabolism ; Skin Neoplasms -- Metabolism ; Tumor Suppressor Proteins -- Physiology
    E-ISSN: 1949-2553
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  • 7
    Language: English
    In: Nucleic acids research, 08 January 2016, Vol.44(1), pp.117-33
    Description: Transcription factor E2F1 is a key regulator of cell proliferation and apoptosis. Recently, it has been shown that aberrant E2F1 expression often detectable in advanced cancers contributes essentially to cancer cell propagation and characterizes the aggressive potential of a tumor. Conceptually, this requires a subset of malignant cells capable of evading apoptotic death through anticancer drugs. The molecular mechanism by which the pro-apoptotic activity of E2F1 is antagonized is widely unclear. Here we report a novel function for EPC1 (enhancer of polycomb homolog 1) in DNA damage protection. Depletion of EPC1 potentiates E2F1-mediated apoptosis in response to genotoxic treatment and abolishes tumor cell motility. We found that E2F1 directly binds to the EPC1 promoter and EPC1 vice versa physically interacts with bifunctional E2F1 to modulate its transcriptional activity in a target gene-specific manner. Remarkably, nuclear-colocalized EPC1 activates E2F1 to upregulate the expression of anti-apoptotic survival genes such as BCL-2 or Survivin/BIRC5 and inhibits death-inducing targets. The uncovered cooperativity between EPC1 and E2F1 triggers a metastasis-related gene signature in advanced cancers that predicts poor patient survival. These findings unveil a novel oncogenic function of EPC1 for inducing the switch into tumor progression-relevant gene expression that may help to set novel therapies.
    Keywords: DNA Damage ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Chromosomal Proteins, Non-Histone -- Genetics ; E2f1 Transcription Factor -- Metabolism ; Neoplasms -- Genetics ; Repressor Proteins -- Genetics
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 8
    Language: English
    In: The Journal of Urology, August 2016, Vol.196(2), pp.570-578
    Description: Penile squamous cell carcinoma is a rare but aggressive cancer. Little is known about pivotal events in tumor pathogenesis and metastasis. Lymph node metastasis is the prevailing prognostic factor while clinical detection in patients remains difficult. Our aim was to identify distinct miRNAs that are differentially expressed in metastatic vs nonmetastatic penile carcinoma, which may serve as diagnostic biomarkers for disease progression. TaqMan® arrays and quantitative polymerase chain reaction were applied to analyze miRNA profiles in penile squamous cell carcinoma specimens and glans tissue from 24 patients. The prognostic value of deregulated miRNAs was analyzed using the Kaplan-Meier method. The Spearman test was applied to determine a potential linkage between distinctive miRNAs in individual patients. Loss of miR-1 (p = 0.0048), miR-101 (p = 0.0001) and miR-204 (p = 0.0004) in metastasizing tumors and associated metastases (p = 0.0151, 0.0019 and 0.0003, respectively) distinguished patients with metastatic and nonmetastatic penile squamous cell carcinoma. These 3 miRNAs showed a coherent expression pattern. Consistently, patients with low levels of all 3 miRNAs had worse survival (p = 0.03). We identified a coordinately regulated miRNA target hub that is over expressed in penile squamous cell carcinoma and associated with lymphovascular invasion. Our results provide evidence of a novel multiple miRNA based signature associated with lymph node metastasis and unfavorable prognosis of penile squamous cell carcinoma. The integrated loss of miR-1, miR-101 and miR-204 may predict the formation of metastases in penile cancer at an early stage.
    Keywords: Penile Neoplasms ; Carcinoma, Squamous Cell ; Neoplasm Metastasis ; Micrornas ; Mortality ; Medicine
    ISSN: 0022-5347
    E-ISSN: 1527-3792
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  • 9
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(6), p.e67091
    Description: Hepatic stellate cells (HSCs) are known as initiator cells that induce liver fibrosis upon intoxication or other noxes. Deactivation of this ongoing remodeling process of liver parenchyma into fibrotic tissue induced by HSCs is an interesting goal to be achieved by targeted genetic modification...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: Biochimica et biophysica acta, January 2014, Vol.1844(1 Pt B), pp.289-98
    Description: A decade of successful results indicates that systems biology is the appropriate approach to investigate the regulation of complex biochemical networks involving transcriptional and post-transcriptional regulations. It becomes mandatory when dealing with highly interconnected biochemical networks, composed of hundreds of compounds, or when networks are enriched in non-linear motifs like feedback and feedforward loops. An emerging dilemma is to conciliate models of massive networks and the adequate description of non-linear dynamics in a suitable modeling framework. Boolean networks are an ideal representation of massive networks that are humble in terms of computational complexity and data demand. However, they are inappropriate when dealing with nested feedback/feedforward loops, structural motifs common in biochemical networks. On the other hand, models of ordinary differential equations (ODEs) cope well with these loops, but they require enormous amounts of quantitative data for a full characterization of the model. Here we propose hybrid models, composed of ODE and logical sub-modules, as a strategy to handle large scale, non-linear biochemical networks that include transcriptional and post-transcriptional regulations. We illustrate the construction of this kind of models using as example a regulatory network centered on E2F1, a transcription factor involved in cancer. The hybrid modeling approach proposed is a good compromise between quantitative/qualitative accuracy and scalability when considering large biochemical networks with a small highly interconnected core, and module of transcriptionally regulated genes that are not part of critical regulatory loops. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology & Clinical Implications. Guest Editor: Yudong Cai.
    Keywords: Cancer ; Chemoresistance ; E2f1 ; Feedback Loop ; Non-Linear Motif ; Signaling ; Models, Theoretical ; Nonlinear Dynamics ; Gene Regulatory Networks -- Genetics ; Signal Transduction -- Genetics
    ISSN: 0006-3002
    ISSN: 15709639
    E-ISSN: 18781454
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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