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Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124

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Title: Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124
Authors: Dong, Peixin Browse this author →KAKEN DB
Xiong, Ying Browse this author
Watari, Hidemichi Browse this author →KAKEN DB
Hanley, Sharon JB Browse this author →KAKEN DB
Konno, Yosuke Browse this author
Ihira, Kei Browse this author
Suzuki, Fumihiko Browse this author →KAKEN DB
Yamada, Takahiro Browse this author →KAKEN DB
Kudo, Masataka Browse this author
Yue, Junming Browse this author
Sakuragi, Noriaki Browse this author →KAKEN DB
Issue Date: 21-Oct-2016
Publisher: Macmillan Publishers
Journal Title: Scientific Reports
Volume: 6
Start Page: 35480
Publisher DOI: 10.1038/srep35480
Abstract: Derepression 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.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 董 培新

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