Extracellular activation of Wnt signaling through epigenetic dysregulation of Wnt inhibitory factor-1 (Wif-1) is associated with pathogenesis of adrenocortical tumor
Metrics: PDF 1352 views | HTML 1844 views | ?
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.