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AutorHipp, Noradc.contributor.author
Aufnahmedatum2016-03-15T10:40:31Zdc.date.accessioned
In OPARU verfügbar seit2016-03-15T10:40:31Zdc.date.available
Jahr der Erstellung2014dc.date.created
ZusammenfassungMYC proto-oncogenes are deregulated in up to 70 % of all human malignancies. Due to their pro-apoptotic function, additional genetic alterations are required to allow for MYC-driven tumorigenesis. In several tumor entities both MYC proteins and survivin, one of the most tumor-specific genes, have been described as unfavorable prognostic markers, but it is unknown whether they cooperate in carcinogenesis. Using Rat-1 fibroblasts as model system, the present study shows that survivin enhanced MYCN-driven anchorage-independent growth and release from contact-inhibition in vitro. Importantly, upon subcutaneous transplantation into mice, cells coexpressing MYCN and survivin generated tumors with shortest latency, increased anaplasia and highest proliferation rate. Increased tumorigenicity was associated with a metabolic switch to aerobic glycolysis (the Warburg effect) and HIF1alpha-linked vascular remodeling. These findings demonstrate that MYCN and survivin cooperate in malignant transformation of fibroblasts, which is relevant for the genesis of several cancers. The pro-survival activity of NF-kappaB signaling pathway plays a key role in controlling initiation and progression of various types of human cancer. Previous studies in our lab have shown that proliferation and survival of MYC-driven B cell lymphomas is incompatible with elevated NF-kappaB activity. To test whether inactivation of NF-kappaB signaling is a general feature of MYC-driven malignancies we established a mouse model of MYC-induced hepatocellular carcinoma (HCC). With a high penetrance and short latency mice developed HCC, which were considerably similar to the human disease. It was not possible to activate NF-kappaB in the tumors - neither via stimulation with TNF-alpha nor via expression of a constitutively active IKK2. These findings imply that MYC-driven cancers actively down-modulate the NF-kappaB pathway and that its forced reactivation might be a treatment option for this subset of malignancies.dc.description.abstract
Spracheendc.language.iso
Verbreitende StelleUniversität Ulmdc.publisher
LizenzStandarddc.rights
Link zum Lizenztexthttps://oparu.uni-ulm.de/xmlui/license_v3dc.rights.uri
SchlagwortSurvivindc.subject
SchlagwortTumorigenesisdc.subject
DDC-SachgruppeDDC 570 / Life sciencesdc.subject.ddc
MeSHCarcinogenesisdc.subject.mesh
MeSHNF-kappa Bdc.subject.mesh
TitelMechanisms of MYC-induced tumorigenesisdc.title
RessourcentypDissertationdc.type
DOIhttp://dx.doi.org/10.18725/OPARU-3290dc.identifier.doi
PPN407623329dc.identifier.ppn
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-vts-90224dc.identifier.urn
GNDMycdc.subject.gnd
GNDNuklearfaktor Kappa Bdc.subject.gnd
FakultätFakultät für Naturwissenschaftenuulm.affiliationGeneral
Datum der Freischaltung2014-06-04T10:55:10Zuulm.freischaltungVTS
Peer-Reviewneinuulm.peerReview
Signatur DruckexemplarW: W-H 13.635uulm.shelfmark
DCMI MedientypTextuulm.typeDCMI
VTS-ID9022uulm.vtsID
KategoriePublikationenuulm.category


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