title: Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124.
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.
authors.affiliation: Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo 0608638, Japan.
authors.forename: Peixin
authors.initials: P
authors.lastname: Dong
authors.affiliation: Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo 0608638, Japan.
authors.forename: Hidemichi
authors.initials: H
authors.lastname: Watari
authors.affiliation: Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo 0608638, Japan.
authors.forename: Sharon Jb
authors.initials: SJ
authors.lastname: Hanley
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo 0608638, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Konno
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo 0608638, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ihira
authors.affiliation: Department of Obstetrics and Gynecology, Tohoku University, Sendai 9808574, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Suzuki
authors.affiliation: Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo 0608638, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo 0608638, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Junming
authors.initials: J
authors.lastname: Yue
authors.affiliation: Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo 0608638, Japan.|Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo 0608638, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sakuragi
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; C119612:PPP1R13L protein, human; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside