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2021-01-26Zeitschriftenartikel
RUNX3 Transcript Variants Have Distinct Roles in Ovarian Carcinoma and Differently Influence Platinum Sensitivity and Angiogenesis
dc.contributor.authorHeinze, Karolin
dc.contributor.authorHölzer, Martin
dc.contributor.authorUngelenk, Martin
dc.contributor.authorGerth, Melanie
dc.contributor.authorThomale, Jürgen
dc.contributor.authorHeller, Regine
dc.contributor.authorMorden, Claire R.
dc.contributor.authorMcManus, Kirk J.
dc.contributor.authorMosig, Alexander S.
dc.contributor.authorDürst, Matthias
dc.contributor.authorRunnebaum, Ingo B.
dc.contributor.authorHäfner, Norman
dc.date.accessioned2024-06-12T15:24:22Z
dc.date.available2024-06-12T15:24:22Z
dc.date.issued2021-01-26none
dc.identifier.other10.3390/cancers13030476
dc.identifier.urihttp://edoc.rki.de/176904/11715
dc.description.abstractThe prognosis of late-stage epithelial ovarian cancer (EOC) patients is affected by chemotherapy response and the malignant potential of the tumor cells. In earlier work, we identified hypermethylation of the runt-related transcription factor 3 gene (RUNX3) as a prognostic biomarker and contrary functions of transcript variants (TV1 and TV2) in A2780 and SKOV3 cells. The aim of the study was to further validate these results and to increase the knowledge about RUNX3 function in EOC. New RUNX3 overexpression models of high-grade serous ovarian cancer (HGSOC) were established and analyzed for phenotypic (IC50 determination, migration, proliferation and angiogenesis assay, DNA damage analysis) and transcriptomic consequences (NGS) of RUNX3 TV1 and TV2 overexpression. Platinum sensitivity was affected by a specific transcript variant depending on BRCA background. RUNX3 TV2 induced an increased sensitivity in BRCA1wt cells (OVCAR3), whereas TV1 increased the sensitivity and induced a G2/M arrest under treatment in BRCA1mut cells (A13-2-12). These different phenotypes relate to differences in DNA repair: homologous recombination deficient A13-2-12 cells show less γH2AX foci despite higher levels of Pt-DNA adducts. RNA-Seq analyses prove transcript variant and cell-line-specific RUNX3 effects. Pathway analyses revealed another clinically important function of RUNX3—regulation of angiogenesis. This was confirmed by thrombospondin1 analyses, HUVEC spheroid sprouting assays and proteomic profiling. Importantly, conditioned media (CM) from RUNX3 TV1 overexpressing A13-2-12 cells induced an increased HUVEC sprouting. Altogether, the presented data support the hypothesis of different functions of RUNX3 transcript variants related to the clinically relevant processes—platinum resistance and angiogenesis.eng
dc.language.isoengnone
dc.publisherRobert Koch-Institut
dc.rights(CC BY 3.0 DE) Namensnennung 3.0 Deutschlandger
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/de/
dc.subjectepithelial ovarian cancereng
dc.subjectRUNX3eng
dc.subjecttranscript variantseng
dc.subjectplatinum resistanceeng
dc.subjectangiogenesiseng
dc.subject.ddc610 Medizin und Gesundheitnone
dc.titleRUNX3 Transcript Variants Have Distinct Roles in Ovarian Carcinoma and Differently Influence Platinum Sensitivity and Angiogenesisnone
dc.typearticle
dc.identifier.urnurn:nbn:de:0257-176904/11715-9
dc.type.versionpublishedVersionnone
local.edoc.container-titlecancersnone
local.edoc.container-issn2072-6694none
local.edoc.pages22none
local.edoc.type-nameZeitschriftenartikel
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-urlhttps://www.mdpi.com/journal/cancersnone
local.edoc.container-publisher-nameMDPInone
local.edoc.container-volume13none
local.edoc.container-issue3none
local.edoc.container-reportyear2021none
dc.description.versionPeer Reviewednone

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