Research Papers:

Extracellular activation of Wnt signaling through epigenetic dysregulation of Wnt inhibitory factor-1 (Wif-1) is associated with pathogenesis of adrenocortical tumor

Yozo Mitsui _, Hiroaki Yasumoto, Taichi Nagami, Miho Hiraki, Naoko Arichi, Noriyoshi Ishikawa, Asuka Araki, Riruke Maruyama, Yuichiro Tanaka, Rajvir Dahiya and Hiroaki Shiina

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Oncotarget. 2014; 5:2198-2207. https://doi.org/10.18632/oncotarget.1889

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Yozo Mitsui1, Hiroaki Yasumoto1, Taichi Nagami1, Miho Hiraki1, Naoko Arichi1, Noriyoshi Ishikawa2, Asuka Araki2, Riruke Maruyama2, Yuichiro Tanaka 3, Rajvir Dahiya3, Hiroaki Shiina1

1 Departments of Urology, Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501 Izumo, Japan

2 Pathology (Organ Pathology Unit), Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501 Izumo, Japan

3 Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California, USA


Yozo Mitsui, email:

Keywords: adrenocortical tumor, Wif-1, epigenetics, Wnt signaling, cyclin D1

Received: March 24, 2014 Accepted: April 07, 2014 Published: April 08, 2014


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-1was 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 through aberrant canonical Wnt/β-catenin signaling activation.

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