DKK3 is a potential tumor suppressor gene in papillary thyroid carcinoma.

The expression of the Dickkopf homolog 3 (DKK3) gene is downregulated in some human cancers, suggesting a possible tumor suppressor role of this gene. The role and regulation of DKK3 in thyroid cancer have not been examined. In this study, we explored the relationship of promoter methylation with the inactivation of DKK3 and tumor behaviors in papillary thyroid carcinoma (PTC). We used methylation-specific PCR and RT-PCR to examine the promoter methylation and expression of DKK3 and tumor characteristics. We found mRNA expression of DKK3 in 44.9% of the PTC tissue samples vs 100% of the matched normal thyroid tissue samples (P<0.01). In contrast, an opposite distribution pattern of DKK3 gene methylation was observed; specifically, 38.8% of the PTC tissue samples vs 0% of the matched normal thyroid tissue samples harbored DKK3 methylation. An inverse correlation between the promoter methylation and mRNA expression of DKK3 in PTC tissue samples was also observed. Moreover, we also found an inverse correlation between DKK3 expression and some aggressive pathological characteristics of PTC, including high TNM stages and lymph node metastasis, but a positive correlation between DKK3 promoter hypermethylation and pathological aggressiveness of the tumor. Treatment of the PTC cell line TPC-1 with the demethylating agent 5-azaC reduced DKK3 promoter methylation and enhanced its expression, establishing functionally the impact of DKK3 methylation on its expression. Our data thus for the first time demonstrate that the DKK3 gene is a potential tumor suppressor gene in thyroid cancer and that aberrant promoter methylation is an important mechanism for its downregulation, which may play a role in the tumorigenesis and aggressiveness of PTC.