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  • 1
    Language: English
    In: The Journal of biological chemistry, 15 April 2016, Vol.291(16), pp.8399-413
    Description: Hepatic stellate cells (HSCs) were recently identified as liver-resident mesenchymal stem cells. HSCs are activated after liver injury and involved in pivotal processes, such as liver development, immunoregulation, regeneration, and also fibrogenesis. To date, several studies have reported candidate pathways that regulate the plasticity of HSCs during physiological and pathophysiological processes. Here we analyzed the expression changes and activity of the RAS family GTPases and thereby investigated the signaling networks of quiescent HSCs versus activated HSCs. For the first time, we report that embryonic stem cell-expressed RAS (ERAS) is specifically expressed in quiescent HSCs and down-regulated during HSC activation via promoter DNA methylation. Notably, in quiescent HSCs, the high level of ERAS protein correlates with the activation of AKT, STAT3, mTORC2, and HIPPO signaling pathways and inactivation of FOXO1 and YAP. Our data strongly indicate that in quiescent HSCs, ERAS targets AKT via two distinct pathways driven by PI3Kα/δ and mTORC2, whereas in activated HSCs, RAS signaling shifts to RAF-MEK-ERK. Thus, in contrast to the reported role of ERAS in tumor cells associated with cell proliferation, our findings indicate that ERAS is important to maintain quiescence in HSCs.
    Keywords: Hippo Pathway ; Raf Kinase ; Embryonic Stem Cell ; Embryonic Stem Cell-Expressed Ras ; Embryonic Stem Cell-Expressed Ras, Eras ; Embryonic Stem Cell-Expressed Ras, Eras, Akt ; Hepatic Stellate Cell (Hsc) ; Mammalian Target of Rapamycin (Mtor) ; Phosphatidylinositide 3-Kinase (PI 3-Kinase) ; Signal Transduction ; DNA Methylation -- Physiology ; Hepatic Stellate Cells -- Enzymology ; MAP Kinase Signaling System -- Physiology ; Oncogene Protein P21(Ras) -- Biosynthesis ; Promoter Regions, Genetic -- Physiology
    E-ISSN: 1083-351X
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(4), p.e0176287
    Description: Many long noncoding RNAs (lncRNAs) are deregulated in cancer and contribute to oncogenesis. In urothelial carcinoma (UC), several lncRNAs have been reported to be overexpressed and proposed as biomarkers. As most reports have not been confirmed...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: European Urology, July 2015, Vol.68(1), pp.3-4
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.eururo.2015.02.034 Byline: Annemarie Greife, Michele J. Hoffmann, Wolfgang A. Schulz Abstract: The Notch pathway, which controls stem cell maintenance and cell differentiation, is activated in certain cancers and therefore constitutes a therapeutic target. Especially in invasive urothelial carcinoma, the pathway is inactivated instead, and drugs inhibiting Notch signaling are likely contra-indicated. Author Affiliation: Department of Urology, Heinrich Heine University Dusseldorf, Dusseldorf, Germany
    Keywords: Medicine
    ISSN: 0302-2838
    E-ISSN: 1873-7560
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  • 4
    In: BJU International, October 2018, Vol.122(4), pp.695-704
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/bju.14415/abstract Byline: Tibor Szarvas, Sabina Sevcenco, Orsolya Modos, David Keresztes, Peter Nyirady, Anita Csizmarik, Robin Ristl, Martin Puhr, Michele J. Hoffmann, Christian Niedworok, Boris Hadaschik, Agnieszka Maj-Hes, Shahrokh F. Shariat, Gero Kramer Keywords: MMP-7; Fas; serum; prognosis; docetaxel; #pcsm; #ProstateCancer Objective To assess the predictive value of pre-chemotherapy matrix metalloproteinase 7 (MMP-7), soluble Fas (sFas) and Fas ligand (FasL) serum levels, as well as their changes during therapy. Patients and Methods Serum levels of MMP-7, Fas and FasL were determined by ELISA in 96 patients with castration-resistant prostate cancer (CRPC): 21 docetaxel-resistant patients who received one single series and 75 docetaxel-sensitive patients who received repeated series of docetaxel. In addition to the 96 pretreatment serum samples, 987 sera collected during chemotherapy were also analysed. Results Higher pretreatment serum MMP-7, sFas and prostate-specific antigen (PSA) levels were significantly associated with both docetaxel resistance (P = 0.007, P = 0.001, P 〈 0.001, respectively) and shorter cancer-specific survival (P 〈 0.001, P = 0.041, P 〈 0.001, respectively). High MMP-7 level remained an independent predictor of both docetaxel resistance (hazard ratio [HR] 2.298, 95% confidence interval [CI]: 1.354-3.899; P = 0.002) and poor cancer-specific survival (HR 2.11, 95% CI: 1.36-3.30; P = 0.001) in multivariable analyses. Greater increase in MMP-7 levels in the second treatment holiday and greater increase in PSA levels in the first and second treatment holidays were predictive of survival. Conclusions Pretreatment serum MMP-7 levels may help to select patients with CRPC who are likely to benefit from docetaxel chemotherapy. Furthermore, MMP-7 levels alone or in combination with PSA levels could be used for therapy monitoring. Correlative studies embedded in clinical trials are necessary to validate these biomarkers for clinical decision-making. CAPTION(S): Fig. S1. Kaplan-Meier survival plots stratified by (A) PSA level and presence of metastasis, by MMP-7 in the subgroup of (B) patients with low PSA & and no metastases and (C) patients with high PSA and metastasis. MMP-7 is significantly associated with survival in both subgroups. Fig. S2. Kaplan-Meier curves of overall survival according to (A) MMP-7-, (B) PSA-changes and (C) their combination during the 2nd treatment-free period ( 2nd holiday). Fig. S3. Changes of PSA (blue lines) and MMP-7 levels (red lines) in representative cases of CRPC. Grey area represents treatment periods (series). Note that PSA and MMP-7 levels elevate prior or at the time of metastatic progression. Table S1. MMP-7, sFas and FasL serum levels at baseline and at time of radiographic progression.
    Keywords: Mmp ‐7 ; Fas ; Serum ; Prognosis ; Docetaxel ; #Pcsm ; #Prostatecancer
    ISSN: 1464-4096
    E-ISSN: 1464-410X
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  • 5
    Language: English
    In: Current Medicinal Chemistry, 2017, Vol.24(37), p.4151-4165
    Description: Histone deacetylases (HDACs) influence diverse cellular processes and may contribute to tumor development and progression by multiple mechanisms. Class I HDACs are often overexpressed in cancers contributing to a genome-wide epigenetic state permitting increased proliferation, and diminished apoptosis and cell differentiation. Class IIA and IIB isoenzymes may likewise contribute to tumorigenesis as components of specific intranuclear repressor complexes or regulators of posttranslational protein modifications. As HDAC inhibitors may counteract these tumorigenic effects several of these compounds are currently tested in clinical trials. 〈/P〉〈P〉 HDAC inhibitors are also considered for urothelial carcinoma, where novel therapeutic drugs are urgently required. However, only modest antineoplastic activity has been observed with isoenzyme-unspecific pan-HDAC inhibitors. Therefore, inhibition of specific HDAC isoenzymes might be more efficacious and tumor-specific. Here, we systematically review knowledge on the expression, function and suitability as therapeutic targets of the 11 classical HDACs in UC. Overall, the class I HDACs HDAC1 and HDAC2 are the most promising targets for antineoplastic treatment. In contrast, targeting HDAC8 and HDAC6 is likely to be of minor relevance in urothelial carcinoma. Class IIA HDACs like HDAC4 require further study, since their downregulation rather than upregulation could be involved in urothelial carcinoma pathogenesis.
    Keywords: Urothelial Carcinoma Bladder Cancer Hdacss Class I Hdacs Targeted Therapy.
    ISSN: 0929-8673
    E-ISSN: 1875-533X
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  • 6
    Language: English
    In: Urologic Oncology: Seminars and Original Investigations, October 2017, Vol.35(10), pp.612-613
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.urolonc.2017.06.017 Byline: Alexander Holscher, Wolfgang A. Schulz, Maria Pinkerneil, Michele J. Hoffmann
    Keywords: Medicine
    ISSN: 1078-1439
    E-ISSN: 1873-2496
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  • 7
    Language: English
    In: Methods in molecular biology (Clifton, N.J.), 2018, Vol.1655, pp.289-317
    Description: Mutations, dysregulation, and dysbalance of epigenetic regulators are especially frequent in urothelial carcinoma (UC) compared to other malignancies. Accordingly, targeting epigenetic regulators may provide a window of opportunity particularly in anticancer therapy of UC. In general, these epigenetic regulators comprise DNA methyltransferases and DNA demethylases (for DNA methylation), histone methyltransferases, and histone demethylases (for histone methylation) as well as acetyl transferases and histone deacetylases (for histone and non-histone acetylation).As epigenetic regulators target a plethora of cellular functions and available inhibitors often inhibit enzymatic activity of more than one isoenzyme or may have further off-target effects, analysis of their functions in UC pathogenesis as well as of the antineoplastic capacity of according inhibitors should follow a multidimensional approach.Here, we present our standard approach for the analysis of the cellular and molecular functions of individual HDAC enzymes, their suitability as treatment targets and for the evaluation of isoenzyme-specific HDAC inhibitors regarding their antineoplastic efficacy. This approach may also serve as prototype for the preclinical evaluation of other epigenetic treatment approaches.
    Keywords: Epigenetics ; Histone Deacetylase Inhibitors ; Histone Deacetylases ; Targeted Therapy ; Urothelial Carcinoma ; Antineoplastic Agents -- Therapeutic Use ; Epigenesis, Genetic -- Drug Effects ; Urologic Neoplasms -- Drug Therapy
    E-ISSN: 1940-6029
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 8
    In: Translational Cancer Research, 8/2018, Vol.7(4), pp.1151-1160
    ISSN: 2218676X
    E-ISSN: 22196803
    Source: CrossRef
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  • 9
    Language: English
    In: Journal of Experimental & Clinical Cancer Research, July 10, 2014, Vol.33(1)
    Description: Background Previous studies have shown that class-I histone deacetylase (HDAC) 8 mRNA is upregulated in urothelial cancer tissues and urothelial cancer cell lines compared to benign controls. Using urothelial cancer cell lines we evaluated whether specific targeting of HDAC8 might be a therapeutic option in bladder cancer treatment. Methods We conducted siRNA-mediated knockdown and specific pharmacological inhibition of HDAC8 with the three different inhibitors compound 2, compound 5, and compound 6 in several urothelial carcinoma cell lines with distinct HDAC8 expression profiles. Levels of HDAC and marker proteins were determined by western blot analysis and mRNA levels were measured by quantitative real-time PCR. Cellular effects of HDAC8 suppression were analyzed by ATP assay, flow cytometry, colony forming assay and migration assay. Results Efficient siRNA-mediated knockdown of HDAC8 reduced proliferation up to 45%. The HDAC8 specific inhibitors compound 5 and compound 6 significantly reduced viability of all urothelial cancer cell lines (IC.sub.50 9 - 21 [mu]M). Flow cytometry revealed only a slight increase in the sub-G1 fraction indicating a limited induction of apoptosis. Expression of thymidylate synthase was partly reduced; PARP-cleavage was not detected. The influence of the pharmacological inhibition on clonogenic growth and migration show a cell line- and inhibitor-dependent reduction with the strongest effects after treatment with compound 5 and compound 6. Conclusions Deregulation of HDAC8 is frequent in urothelial cancer, but neither specific pharmacological inhibition nor siRNA-mediated knockdown of HDAC8 impaired viability of urothelial cancer cell lines in a therapeutic useful manner. Accordingly, HDAC8 on its own is not a promising drug target in bladder cancer. Keywords: Histone deacetylase 8, Histone deacetylase inhibitor, Urothelial bladder cancer, Cell cycle arrest
    Keywords: Cancer Research -- Comparative Analysis ; Cancer Research -- Health Aspects
    ISSN: 0392-9078
    E-ISSN: 17569966
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  • 10
    Language: English
    In: Tumor Biology, 2016, Vol.37(2), pp.1763-1769
    Description: According to GLOBOCAN 2012, the worldwide burden of cancer increased and is expected to worsen within the next decades. Therefore, universal combat against cancer will not succeed with treatment solely; effective prevention and early detection are urgently needed to tackle the cancer crisis. Emerging data demonstrate that long non-coding RNAs are involved in numerous biological and pathological processes like development and differentiation and in a variety of human diseases including cancer. Located at 18q21, LINC-ROR (regulator of reprogramming) is a modulator of ESCs maintenance and hypoxia-signaling pathways in hepatocellular cancer cells. The aim of this study was to examine the expression of LINC-ROR in various cell lines and representative samples of human cancers by quantitative real-time RT-PCR to provide a snapshot on how LINC-ROR expression may be deregulated in cancer. More than 30 cell lines and 112 patient specimens from various tissues were assessed for relative expression of LINC-ROR . Our results revealed that the expression of LINC-ROR was lower in all somatic cancer cell lines compared to stem cells or cells with stem cell-like capabilities, like the embryonic carcinoma cell line, NTERA-2. In tissues, expression patterns vary, but some cancerous tissues displayed increased LINC-ROR expression compared to corresponding normal tissues. Thus, we hypothesize that LINC-ROR may have a key function in a subpopulation of cells from the tumor bulk, i.e., the cancer stem cells associated with specific properties including resistance to adverse environmental conditions.
    Keywords: Long non-coding RNAs ; LINC-ROR ; Gene expression ; Cancer
    ISSN: 1010-4283
    E-ISSN: 1423-0380
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