2024-03-28T11:29:31Zhttps://eprints.lib.hokudai.ac.jp/dspace-oai/requestoai:eprints.lib.hokudai.ac.jp:2115/631702022-11-17T02:08:08Zhdl_2115_20040hdl_2115_121Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124Dong, PeixinXiong, YingWatari, HidemichiHanley, Sharon JBKonno, YosukeIhira, KeiSuzuki, FumihikoYamada, TakahiroKudo, MasatakaYue, JunmingSakuragi, Noriaki490Derepression of wild-type p53 by suppressing its negative inhibitor iASPP (Inhibitor of apoptosis-stimulating protein of p53) represents a potential therapeutic option for cervical cancer (CC). Here, we reported a novel functional significance of iASPP upregulation in cervical tumorigenesis: iASPP acts as a key promoter of CC cell proliferation, epithelial-mesenchymal transition, invasion and cancer stemness, by interacting with p53 to suppress p53-mediated transcription of target genes and reducing p53-responsive microRNA-34a levels. Moreover, we demonstrate that miR-124, directly targeting iASPP, reduces expression of iASPP and attenuates CC cell growth and invasiveness. Low miR-124 expression is inversely correlated with increased expression of iASPP mRNA in CC tissues. In a cohort of 40 patients with CC, the low miR-124 expression was correlated with poor 5-year overall survival (P = 0.0002) and shorter disease-free survival 5-year (P = 0006). Treatment with the DNA methyltransferase inhibitor Zebularine increases miR-124 expression and retards CC cell growth and invasion with minimal toxicity to normal cells. Even at a non-toxic concentration, Zebularine was effective in suppressing CC cell invasion and migration. Altogether, the restoration of miR-124 reduces iASPP expression and leads to p53-dependent tumor suppression, suggesting a therapeutic strategy to treat iASPP-associated CC.Macmillan PublishersJournal Articleapplication/pdfapplication/pdfhttp://hdl.handle.net/2115/63170https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/63170/2/Final_PDF_iASPP.pdfhttps://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/63170/3/srep35480-s1.pdf2045-2322Scientific Reports6354802016-10-21enginfo:doi/10.1038/srep35480https://creativecommons.org/licenses/by/4.0/publisher