title: Extracellular activation of Wnt signaling through epigenetic dysregulation of Wnt inhibitory factor-1 (Wif-1) is associated with pathogenesis of adrenocortical tumor.
abstract: Wnt/β-catenin signaling is considered to be an essential regulator of adrenocortical oncogenesis. Wnt inhibitory factor-1 (Wif-1), an extracellular regulator of Wnt signaling, is frequently down-regulated by hypermethylation of the promoter CpG. We investigated epigenetic regulation of Wif-1 and its association with adrenocortical (AC) tumor pathogenesis in light of Wnt activation. The AC tumors showed a high prevalence of Wif-1 promoter methylation and low prevalence of Wif-1 mRNA transcription as compared to the normal adrenal (NA) samples. Furthermore, a significant correlation was found between Wif-1 promoter methylation and mRNA transcription in the tumors. Either intracellular β-catenin accumulation or β-catenin mRNA transcription was significantly elevated in the AC tumors, which also showed an inverse correlation with Wif-1 mRNA transcription. Cyclin D1, a target gene of Wnt signaling, was also up-regulated in the AC tumors as compared with the NA samples. In addition, down-regulation of Wif-1 was correlated with increased cyclin D1 at both mRNA and protein levels. However, despite the proposed activation of Wnt signaling in AC tumors, only 2 of 20 with intracellular β-catenin accumulation showed β-catenin mutations. Thus, genetic alterations of β-catenin and epigenetics-related Wif-1 promoter hypermethylation may be important mechanisms underlying AC tumor formation though aberrant canonical Wnt/β-catenin signaling activation.
authors.affiliation: Departments of Urology, Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501 Izumo, Japan.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Mitsui
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yasumoto
authors.forename: Taichi
authors.initials: T
authors.lastname: Nagami
authors.forename: Miho
authors.initials: M
authors.lastname: Hiraki
authors.forename: Naoko
authors.initials: N
authors.lastname: Arichi
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Asuka
authors.initials: A
authors.lastname: Araki
authors.forename: Riruke
authors.initials: R
authors.lastname: Maruyama
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiina
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics*; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D012097:Repressor Proteins; C485569:WIF1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin
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