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Heparanase confers a growth advantage to differentiating embryonic stem cells, and enhances their differentiation into oligodendrocytes
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
URN: urn:nbn:se:uu:diva-265309OAI: oai:DiVA.org:uu-265309DiVA, id: diva2:865106
Tillgänglig från: 2015-10-26 Skapad: 2015-10-26 Senast uppdaterad: 2016-01-13
Ingår i avhandling
1. Novel Regulators of Brain Tumor Development: – From neural stem cell differentiation to in vivo models
Öppna denna publikation i ny flik eller fönster >>Novel Regulators of Brain Tumor Development: – From neural stem cell differentiation to in vivo models
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Malignant brain tumors are diseases with poor prognosis and/or severe long-term side effects of treatment. This thesis aimed to discover novel regulators in brain tumor development, based on studying neural stem cell and progenitor cell (NSPC) differentiation and using animal models to introduce new insights to mechanisms of human brain tumors.

The enzyme heparanase (HPSE) that degrades heparan sulfate (HS) is active in cell signaling and ECM remodeling. In paper I, we found an enhanced differentiation to oligodendrocytes in ES cell-derived NSPCs overexpressing HPSE. Further analysis suggested that this enhanced formation of oligodendrocytes was associated with alterations in receptor tyrosine kinase signaling, and that HPSE might also exert anti-apoptotic functions.

Subsequently, in paper II we studied the involvement of HPSE in glioma development. We observed that high HPSE levels associated with poor survival in glioma patients. In experimental models, we found that HPSE promoted glioma growth, and that an inhibitor of HPSE reduced glioma progression both in vitro and in vivo.

We hypothesize that regulators in NSPC differentiation could have a potential role in brain tumor development. In paper III, we explored the function of NRBP2, a pseudokinase that is up-regulated during NSPC differentiation. We found low expression of NRBP2 in brain tumors, in comparison to normal brain. In medulloblastoma, in particular, low NRBP2 expression is linked to poor prognosis. Overexpression of NRBP2 in medulloblastoma cells led to impaired cell growth and migration, concomitant with an increased cell death.

In paper IV, we searched for novel glioma susceptibility genes by sequencing dog breeds from the same ancestor but with different glioma incidence. In this way we identified three new glioma-associated genes. Two of these are significantly regulated in human glioma and one of those might have a role in glioblastoma stem cell differentiation.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2015. s. 66
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1155
Nyckelord
glioma, medulloblastoma, neural stem cell, heparanase, NRBP2, dog models, susceptibility
Nationell ämneskategori
Cell- och molekylärbiologi Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-264470 (URN)978-91-554-9394-3 (ISBN)
Disputation
2015-12-15, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöld vag 20, Uppsala, 09:15 (Engelska)
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Handledare
Tillgänglig från: 2015-11-23 Skapad: 2015-10-13 Senast uppdaterad: 2018-01-10

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Xiong, Anqi
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Institutionen för immunologi, genetik och patologi
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

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