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.authoridDidem Karakaş Zeybek / 0000-0002-3781-6834en_US
dc.authorscopusidDidem Karakaş Zeybek / 56422040600
dc.authorwosidDidem Karakaş Zeybek / L-6682-2018
dc.contributor.authorBayraktar, Recep
dc.contributor.authorIvan, Cristina
dc.contributor.authorBayraktar, Emine
dc.contributor.authorKanlıkılıçer, Pınar
dc.contributor.authorKabil, Nashwa N.
dc.contributor.authorKahraman, Nermin
dc.contributor.authorMokhlis, Hamada A.
dc.contributor.authorKarakaş Zeybek, Didem
dc.contributor.authorRodriguez-Aguayo, Cristian
dc.contributor.authorArslan, Ahmet
dc.contributor.authorSheng, Jianting
dc.contributor.authorWong, Stephen
dc.contributor.authorLopez-Berestein, Gabriel
dc.contributor.authorCalin, George A.
dc.contributor.authorÖzpolat, Bülent
dc.date.accessioned2020-08-30T20:07:23Z
dc.date.available2020-08-30T20:07:23Z
dc.date.issued2018
dc.departmentİstinye Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümüen_US
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.en_US
dc.description.sponsorshipNIH/NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R21CA199050, P30CA016672]; noncoding RNA centeren_US
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.en_US
dc.identifier.citationBayraktar, R., Ivan, C., Bayraktar, E., Kanlikilicer, P., Kabil, N. N., Kahraman, N., ... & Sheng, J. (2018). Dual suppressive effect of miR-34a on the FOXM1/eEF2-kinase axis regulates triple-negative breast cancer growth and invasion. Clinical Cancer Research, 24(17), 4225-4241.en_US
dc.identifier.doi10.1158/1078-0432.CCR-17-1959en_US
dc.identifier.endpage4241en_US
dc.identifier.issn1078-0432en_US
dc.identifier.issn1557-3265en_US
dc.identifier.issue17en_US
dc.identifier.pmid29748184en_US
dc.identifier.scopus2-s2.0-85052735224en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage4225en_US
dc.identifier.urihttps://doi.org/10.1158/1078-0432.CCR-17-1959
dc.identifier.urihttps://hdl.handle.net/20.500.12713/753
dc.identifier.volume24en_US
dc.identifier.wosWOS:000444040400019en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.institutionauthorKarakaş Zeybek, Didemen_US
dc.language.isoenen_US
dc.publisherAmer Assoc Cancer Researchen_US
dc.relation.ispartofClinical Cancer Researchen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.titleDual suppressive effect of miR-34a on the FOXM1/eEF2-kinase axis regulates triple-negative breast cancer growth and invasionen_US
dc.typeArticleen_US

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