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

• Dong, Peixin

• Xiong, Ying

• Watari, Hidemichi

• Hanley, Sharon JB

• Konno, Yosuke

• Ihira, Kei

• Suzuki, Fumihiko

• Yamada, Takahiro

• Kudo, Masataka

• Yue, Junming

• Sakuragi, Noriaki

抄録

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.

収録刊行物

• Scientific Reports

  Scientific Reports 6 35480-, 2016-10-21

  Macmillan Publishers

詳細情報

• CRID: 1050282677653215488
• NII論文ID: 120005851099
• HANDLE: 2115/63170
• ISSN: 20452322
• 本文言語コード: en
• 資料種別: journal article
• データソース種別:
  • IRDB
  • CiNii Articles