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

// Yozo Mitsui 1 , Hiroaki Yasumoto 1 , Taichi Nagami 1 , Miho Hiraki 1 , Naoko Arichi 1 , Noriyoshi Ishikawa 2 , Asuka Araki 2 , Riruke Maruyama 2 , Yuichiro Tanaka 3 , Rajvir Dahiya 3 , Hiroaki Shiina 1 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 Correspondence: 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 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-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.