Dual Suppressive Effect of miR-34a on the FOXM1/eEF2-Kinase Axis Regulates Triple-Negative Breast Cancer Growth and Invasion

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dc.authorid0000-0002-3781-6834
dc.authorid0000-0003-3360-6319
dc.authorid0000-0002-5189-1507
dc.authorid0000-0002-8227-2055
dc.authorid0000-0002-7880-7723
dc.authorid0000-0001-6704-5615
dc.authorid0000-0002-7427-0578
dc.authorscopusid37036763600
dc.authorscopusid36628618800
dc.authorscopusid56051682000
dc.authorscopusid35100471200
dc.authorscopusid55990905500
dc.authorscopusid56711736000
dc.authorscopusid57226459580
dc.authorwosidKarakas, Didem/L-6682-2018
dc.authorwosidCalin, George/E-9390-2011
dc.authorwosidMOKHLIS, HAMADA/ABB-6198-2021
dc.contributor.authorBayraktar, Recep
dc.contributor.authorIvan, Cristina
dc.contributor.authorBayraktar, Emine
dc.contributor.authorKanlikilicer, Pınar
dc.contributor.authorKabil, Nashwa N.
dc.contributor.authorKahraman, Nermin
dc.contributor.authorÖzpolat, Bülent
dc.contributor.authorArslan, Ahmet
dc.date.accessioned2022-05-11T14:41:13Z
dc.date.available2022-05-11T14:41:13Z
dc.date.issued2018
dc.departmentFakülteler, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Tıbbi Genetik Ana Bilim Dalı
dc.description.abstractPurpose: Recent studies indicated that dysregulation of noncoding KNAs (ncRNA) such as miRNAs is involved in pathogenesis of various human cancers. However, the molecular mechanisms underlying miR-34a are not fully understood in triple-negative breast cancer (TNBC). Experimental Design: We performed in vitro functional assays on TNBC cell lines to investigate the role of mi R-34a in FOLM1/eEF2K signaling axis. TNBC tumor xenograft models were used for in vivo therapeutic delivery of miR-34a. Results: In this study, we investigated the role of p53-driven ncRNA miR-34a and found that miR-34a is associated with significantly longer patient survival in TNBC and inversely correlated with levels of proto-oncogenic eEF2K, which was associated with significantly shorter overall patient survival, We showed that miR-34a directly binds to the 3'-untranslated region of eEF2K and FOXM1 mRNAs and suppresses their expression, leading to inhibition of TNBC cell proliferation, motility, and invasion. Notably, restoring miR-34a expression recapitulated the effects of inhibition of eEF2K and FOXM1, the transcription factor for eEF2K and the direct target of p53, in TNBC cell lines, whereas overexpression of eEF2K and FOXM1 rescued the effects and signaling pathways mediated by miR-34a. Moreover, in vivo therapeutic delivery of miR-34a nanopartides by systemic intravenous administration delayed tumor growth of two different orthotopic TNBC tumor xenograft models by inhibiting eEF2K and FOXM1, intratumoral proliferation and angiogenesis, and inducing apoptosis. Conclusions: Overall, our findings provide new insights into the tumor suppressor role of miR-34a by dual-targeting of FOXM1/eEF2K signaling axis and suggest that miR-34a-based gene therapy may be a potential therapeutic strategy in TNBC. (C)2018 AACR.
dc.description.sponsorshipNIH/NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R21CA199050, P30CA016672]; noncoding RNA center; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA016672] Funding Source: NIH RePORTER
dc.description.sponsorshipThis work was supported in part by grants from the NIH/NCI (R21CA199050 and P30CA016672) and the funding from noncoding RNA center and used the Functional Proteomics RPPA Core Facility.
dc.identifier.doi10.1158/1078-0432.CCR-17-1959
dc.identifier.endpage4241
dc.identifier.issn1078-0432
dc.identifier.issn1557-3265
dc.identifier.issue17en_US
dc.identifier.pmid29748184
dc.identifier.scopus2-s2.0-85052735224
dc.identifier.scopusqualityQ1
dc.identifier.startpage4225
dc.identifier.urihttps://doi.org/10.1158/1078-0432.CCR-17-1959
dc.identifier.urihttps://hdl.handle.net/20.500.11776/9112
dc.identifier.volume24
dc.identifier.wosWOS:000444040400019
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorArslan, Ahmet
dc.language.isoen
dc.publisherAmer Assoc Cancer Research
dc.relation.ispartofClinical Cancer Research
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectFactor 2 Kinase
dc.subjectTumor-Suppressor
dc.subjectElongation
dc.subjectCells
dc.subjectApoptosis
dc.subjectFoxm1
dc.subjectExpression
dc.subjectFamily
dc.subjectTarget
dc.subjectProliferation
dc.titleDual Suppressive Effect of miR-34a on the FOXM1/eEF2-Kinase Axis Regulates Triple-Negative Breast Cancer Growth and Invasion
dc.typeArticle

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