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.
Highlights
Adrenocortical (AC) tumors can be classified as either a benign AC adenoma or AC carcinoma
Cyclin D1 mRNA transcription was enhanced in AC tumors as compared to the normal adrenal (NA) samples (Fig. 1C-3, p
We found abnormal β-catenin staining in approximately half of the AC tumors
Summary
Adrenocortical (AC) tumors can be classified as either a benign AC adenoma or AC carcinoma The former is a common disorder of the adrenal glands with a prevalence of 3-10% of the general population, whereas AC carcinomas are extremely rare, with an estimated annual incidence of 1-2 cases per 1 million individuals in the United States [1, 2]. Under inactivation of Wnt signaling, β-catenin is normally phosphorylated at the NH2-terminal residues, in which a glycogen synthase kinase 3β (GSK-3β) consensus motif is present, with the aid of a scaffolding complex www.impactjournals.com/oncotarget composed of axin and adenomatous polyposis proteins (APCs). Under activation of Wnt signaling with the cooperation of Wnt proteins bound to their frizzled transmembrane receptors, the functional loss of GSK-3β is a common event, namely, failure to phosphorylate β-catenin. Non-phosphorylated forms of β-catenin can accumulate in the cytoplasm, enter the nucleus, and activate the Wnt target genes c-myc and cyclin D1 as a transcriptional activator with the aid of TCF/LEF family proteins [9,10,11]
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