Aberrant WNT/β-catenin signaling in parathyroid carcinoma.

Abstract

BACKGROUND:

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. The molecular etiology of PC is poorly understood.

RESULTS:

The 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.

CONCLUSION:

Aberrant 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.

• Authors: Jessica Svedlund, Maria Aurén, Magnus Sundström, Henning Dralle, Göran Akerström, Peyman Björklund, Gunnar Westin
• Journal: Molecular cancer (Mol Cancer) Vol. 9 Pg. 294 (Nov 15 2010) ISSN: 1476-4598 [Electronic] England
• PMID: 21078161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenomatous Polyposis Coli Protein
• Wnt Proteins
• beta Catenin

Topics

• Adenomatous Polyposis Coli Protein (genetics, metabolism)
• Blotting, Western
• DNA Methylation
• Humans
• Immunohistochemistry
• In Vitro Techniques
• Parathyroid Neoplasms (genetics, metabolism, microbiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (genetics, physiology)
• Tumor Cells, Cultured
• Wnt Proteins (genetics, metabolism)
• beta Catenin (genetics, metabolism)