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Analysis of microRNAs implicated in the regulation of NF-kB and MGMT pathways for their role in conferring apoptosis and chemoresistance of glioma tumours

English title Analysis of microRNAs implicated in the regulation of NF-kB and MGMT pathways for their role in conferring apoptosis and chemoresistance of glioma tumours
Applicant Vassella Erik
Number 138129
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pathologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Experimental Cancer Research
Start/End 01.04.2012 - 31.05.2015
Approved amount 301'856.00
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All Disciplines (3)

Discipline
Experimental Cancer Research
Molecular Biology
Cellular Biology, Cytology

Keywords (4)

Gliom; MicroRNA; Temozolomid-Resistenz; NF-kB

Lay Summary (German)

Lead
Lay summary

MicroRNAs sind kurze, endogene RNA-Fragmente, die eine neu entdeckte Familie von Regulatoren der Genexpression auf der posttranskriptionellen Ebene bilden und in unterschiedlichen biologischen Prozessen, wie zum Beispiel Zellteilung, Differenzierung und Apoptose eine wichtige Rolle spielen. Sie sind massgeblich an der Entstehung und Progression von Tumoren beteiligt. Das zentrale Ziel unserer Arbeit ist, MicroRNAs zu identifizieren, welche Chemoresistenzgene glialer Tumoren regulieren. Diese Tumoren gehören zu den häufigsten und bösartigsten Hirntumoren im Erwachsenenalter und sprechen häufig schlecht auf Chemotherapie an.  Wir fokusieren uns auf MicroRNAs, die aufgrund von Computerprediktionen als mögliche Regulatoren bekannter Chemoresistenzgene gelten. Insbesondere wollen wir O6-Methylguanine-DNA-methyltransferase (MGMT) sowie verschiedene Komponenten des NF-kB-Uebertragungswegs, die bei der Resistenzentwicklung gegenüber alkylierenden Agentien beteiligt sind, näher untersuchen. In einem weiteren Approach werden Glioma-Zellen mit einer MicroRNA-Bibliothek im lentiviralen Vektorsystem transduziert und nach solchen MicroRNAs selektioniert, die Resistenz gegenüber alkylierenden Agentien vermitteln.  Interessante MicroRNAs werden darauf hin untersucht, ob sie in Tumoren dysreguliert und in Apoptoseprozessen beteiligt sind. Expressionsdaten werden mit klinischen Daten des Patienten korreliert. Zudem sollen die molekularen Mechanismen, die zu einer veränderten Expression führen, näher charakterisiert werden.  Am glialen Zelllinienmodell soll untersucht werden, welcher Einfluss die Höhe der Expression dieser MicroRNAs auf die Chemoresistenz der Tumorzelllinien hat. Zudem sollen potentielle Targets dieser MicroRNAs näher untersucht werden. MicroRNAs, die die Chemoresistenz von Gliomen beeinflussen, können möglicherweise in Zukunft als Zielmoleküle adjuvanter Chemotherapie eingesetzt werden.


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Anaplastic oligodendroglioma arising from the brain stem and featuring 1p/19q co-deletion.
Hewer Ekkehard, Beck Jürgen, Vassella Erik, Vajtai Istvan (2014), Anaplastic oligodendroglioma arising from the brain stem and featuring 1p/19q co-deletion., in Neuropathology : official journal of the Japanese Society of Neuropathology, 34(1), 32-8.
miR-125b controls apoptosis and temozolomide resistance by targeting TNFAIP3 and NKIRAS2 in glioblastomas.
Haemmig S, Baumgartner U, Glück A, Zbinden S, Tschan M P, Kappeler A, Mariani L, Vajtai I, Vassella E (2014), miR-125b controls apoptosis and temozolomide resistance by targeting TNFAIP3 and NKIRAS2 in glioblastomas., in Cell death & disease, 5, 1279-1279.
Polymorphous oligodendroglioma of Zülch revisited: a genetically heterogeneous group of anaplastic gliomas including tumors of bona fide oligodendroglial differentiation.
Hewer Ekkehard, Beck Jürgen, Murek Michael, Kappeler Andreas, Vassella Erik, Vajtai Istvan (2014), Polymorphous oligodendroglioma of Zülch revisited: a genetically heterogeneous group of anaplastic gliomas including tumors of bona fide oligodendroglial differentiation., in Neuropathology : official journal of the Japanese Society of Neuropathology, 34(4), 323-32.
IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival.
Leu Severina, von Felten Stefanie, Frank Stephan, Vassella Erik, Vajtai Istvan, Taylor Elisabeth, Schulz Marianne, Hutter Gregor, Hench Jürgen, Schucht Philippe, Boulay Jean-Louis, Mariani Luigi (2013), IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival., in Neuro-oncology, 15(4), 469-79.
Rosette-forming glioneuronal tumor of the cerebellum in statu nascendi: an incidentally detected diminutive example indicates derivation from the internal granule cell layer.
Thommen François, Hewer Ekkehard, Schäfer Stephan C, Vassella Erik, Kappeler Andreas, Vajtai Istvan (2013), Rosette-forming glioneuronal tumor of the cerebellum in statu nascendi: an incidentally detected diminutive example indicates derivation from the internal granule cell layer., in Clinical neuropathology, 32(5), 370-6.
Incongruous differential immunoexpression of the MGMT protein in a double adenoma of the pituitary with homogeneous nonmethylated MGMT promoter genotype.
Galli Serena, Kappeler Andreas, Vassella Erik, Sahli Rahel, Vajtai Istvan (2012), Incongruous differential immunoexpression of the MGMT protein in a double adenoma of the pituitary with homogeneous nonmethylated MGMT promoter genotype., in Clinical neuropathology, 31(2), 99-103.
Sarcomatous evolution of oligodendroglioma ("oligosarcoma"): confirmatory report of an uncommon pattern of malignant progression in oligodendroglial tumors.
Vajtai Istvan, Vassella Erik, Hewer Ekkehard, Kappeler Andreas, Reinert Michael M (2012), Sarcomatous evolution of oligodendroglioma ("oligosarcoma"): confirmatory report of an uncommon pattern of malignant progression in oligodendroglial tumors., in Pathology, research and practice, 208(12), 750-5.

Collaboration

Group / person Country
Types of collaboration
PD Dr. Mario Tschan, DKF Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. L. Mariani and Dr. J. L. Boulay Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Philippe Schucht Switzerland (Europe)
- Publication
PD Dr. Stephan Frank Switzerland (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EACR 2014 Poster miR-125b confers temozolomide resistance by targeting TNFAIP3 in glioma tumours 06.07.2014 Munich, Germany Haemmig Stefan; Vassella Erik;
MicroRNA Europe 2013 Talk given at a conference microRNAs implicated in the regulation of NF-kappa B signalling in glioma tumours 05.11.2013 Cambridge, Great Britain and Northern Ireland Vassella Erik;
AACR 2013 Poster microRNAs implicated in the regulation of NF-kB activity in gioma tumours 09.04.2013 Washington, United States of America Vassella Erik; Haemmig Stefan;
EACR 2012 Poster MICRORNAS IMPLICATED IN THE REGULATION OF NF-κB ACTIVITY IN GLIOMA TUMOURS 09.07.2012 Barcelona, Spain Vassella Erik;


Associated projects

Number Title Start Funding scheme
164097 Nanoparticle Tracking Analysis using NanoSight NS300 instrument 01.12.2015 R'EQUIP
175656 Role of PP2A phosphatase and miR-19b in DNA damage response and temozolomide / radiotherapy resistance of glioblastoma tumours 01.03.2018 Project funding (Div. I-III)
118039 Role of microRNAs in tumourigenesis and chemoresistance in lung cancer and glioma 01.01.2008 Project funding (Div. I-III)

Abstract

Background: microRNAs (miRNAs) are short regulatory sequences that constitute a new layer of gene expression at the post-transcriptional level. They play key roles in cell fate specification, proliferation and cell death and function as tumour suppressors or oncogenes. We plan to investigate, if some of these miRNAs confer chemoresistance of gliomas. These brain tumours are among the most prognostically discouraging neoplasia in human and there is basically no curative option for glioma patients.Working hypothesis: miRNAs are implicated in conferring resistance to chemotherapy in gliomas. Specific aims: O6-methylguanine-DNA-methyltransferase (MGMT) and nuclear factor ?B (NF-?B) are two key effectors associated with the development of resistance to alkylating agent-based chemotherapy in glioma tumours. It was shown previously that NF-?B plays an important role in MGMT regulation, indicating that these two pathways are linked, but the underlying molecular mechanisms, leading to dysregulation of these pathways in gliomas, are poorly understood. The aim of this work is to investigate microRNAs that interfere with these pathways for their role in conferring chemoresistance, apoptosis and proliferation of glioma tumours.Experimental design: The project is divided into two parts. In a first part, we aim to identify microRNAs that affect the expression of components of the NF-?B pathway and MGMT, and will investigate these miRNAs for their role in proliferation, apoptosis and chemoresistance of glioma cell lines. We were able to show that the intracellular NF-?B activity is significantly increased upon transfection of glioma cells with miR-125a precursor. This can be, in part, explained by our finding that TNFAIP3, a negative regulator of this pathway, is directly targeted by miR-125a. However, the expression of other negative regulatory components of the NF-?B pathway may also be affected by miR-125a, which will be further analysed. In addition, we plan to investigate if there is a link between the activity of NF-?B and the expression of MGMT and if the latter gene is also regulated by microRNAs. Interesting miRNA candidates will be analysed for their expression in tissues of low grade gliomas from the archive of the institute of pathology of Bern and the institute of pathology of Basel. The results of this analysis will be correlated with target gene expression, the glioma patients’ overall survival, tumour progression and response to chemotherapy. In a second part of this project, we will perform a functional screening of glioma cells transduced with a lentiviral miRNA library for miRNAs conferring temozolomide resistance. In parallel, microRNAs that are differentially regulated between chemosensitive and chemoresistant low grade gliomas will be identified by expression profiling (supported by the Bernese Cancer league). Those microRNAs identified by the functional screening that are differentially regulated between chemosensitive and chemoresistant tumours are most promising candidates for conferring chemoresistance in glioma tumours. Experiments are planed similar to those described for miR-125a, to further characterize these miRNAs.Expected value of the proposed project: The experiments described in the research proposal may provide important information about the role of miRNAs in conferring proliferation, apoptosis and chemoresistance of gliomas. In future, some of these miRNAs might be used as predictive markers for chemotherapy or prognostic markers for survival. In addition, overexpressing some of these miRNAs or antisense miRNAs might potentially be used in adjuvant therapy for the treatment of glioma patients.
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