Aberrant WNT/β-catenin signaling in parathyroid carcinoma

Jessica Svedlund,Magnus Sundström,Henning Dralle,Maria Aurén,Peyman Björklund,Gunnar Westin,Göran Åkerström

doi:10.1186/1476-4598-9-294

Jessica Svedlund, Magnus Sundström + Show 5 more

Open Access

https://doi.org/10.1186/1476-4598-9-294

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Abstract

BackgroundParathyroid carcinoma (PC) is a very rare malignancy with a high tendency to recur locally, and recurrent disease is difficult to eradicate. In most western European countries and United States, these malignant neoplasms cause less than 1% of the cases with primary hyperparathyroidism, whereas incidence as high as 5% have been reported from Italy, Japan, and India. The molecular etiology of PC is poorly understood.ResultsThe APC (adenomatous polyposis coli) tumor suppressor gene was inactivated by DNA methylation in five analyzed PCs, as determined by RT-PCR, Western blotting, and quantitative bisulfite pyrosequencing analyses. This was accompanied by accumulation of stabilized active nonphosphorylated β-catenin, strongly suggesting aberrant activation of the WNT/β-catenin signaling pathway in these tumors. Treatment of a primary PC cell culture with the DNA hypomethylating agent 5-aza-2'-deoxycytidine (decitabine, Dacogen(r)) induced APC expression, reduced active nonphosphorylated β-catenin, inhibited cell growth, and caused apoptosis.ConclusionAberrant WNT/β-catenin signaling by lost expression and DNA methylation of APC, and accumulation of active nonphosphorylated β-catenin was observed in the analyzed PCs. We suggest that adjuvant epigenetic therapy should be considered as an additional option in the treatment of patients with recurrent or metastatic parathyroid carcinoma.

Highlights

Parathyroid carcinoma (PC) is a very rare malignancy with a high tendency to recur locally, and recurrent disease is difficult to eradicate
adenomatous polyposis coli (APC) promoter hypermethylation in parathyroid carcinoma In order to determine whether expression of APC was perturbed in the five PC specimens, RT-PCR analysis was performed
The results showed that APC mRNA expression was undetectable to very low in the PCs when compared to parathyroid adenomas or normal parathyroid tissue specimens (Figure 1A)

Summary

Introduction

Parathyroid carcinoma (PC) is a very rare malignancy with a high tendency to recur locally, and recurrent disease is difficult to eradicate. In most western European countries and United States, these malignant neoplasms cause less than 1% of the cases with primary hyperparathyroidism, whereas incidence as high as 5% have been reported from Italy, Japan, and India. In most western European countries and United States, these malignant neoplasms cause less 1% of the cases, whereas incidence as high as 5% have been reported from Italy, Japan, and India [1,2,3,4]. PCs are slow-growing with a high tendency to recur locally (30%-50%), and recurrent disease is difficult to eradicate [6,7,8]. The HRPT2 mutation frequency in sporadic parathyroid adenoma was calculated to 1.8% [15]

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