title: Restoration of miR-34a in p53 deficient cells unexpectedly promotes the cell survival by increasing NFκB activity.
abstract: Upregulation of miR-34a by p53 is recently believed to be a key mediator in the pro-apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR-34a levels in p53 deficient cells could rescue the response to DNA damage. Compared with the p53 wildtype U2OS cells, miR-34a expression was much lower in p53 deficient Saos2 cells upon cisplatin treatment. Unexpectedly, delivery of miR-34a in Saos2 cells does not increase the cell sensitivity to apoptosis. This effect was mediated by direct downregulation of SirT1 expression by miR-34a, which in turn increased the NFκB activity. Inhibition of NFκB activity in Saos2 cells by Aspirin sensitized the miR-34a overexpressing cells to cell death. Thus, in tumors with p53 deficiency, miR-34a restoration alone confers drug resistance through Sirt1-NFκB pathway and combination of miR-34a and NFκB inhibitor could be considered as a promising therapeutic strategy.
authors.affiliation: Department of Stomatology, Guangzhou General Hospital of Guangzhou Military Command, 111 Liuhua Road, Guangzhou 510010, People's Republic of China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Tan
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Mao
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Liwei
authors.initials: L
authors.lastname: Zheng
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.forename: Yinzhong
authors.initials: Y
authors.lastname: Duan
authors.forename: Zuolin
authors.initials: Z
authors.lastname: Jin
authors.forename: Wei
authors.initials: W
authors.lastname: Kuang
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53