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Published on: August 23, 2019
DKK3 is a potential tumor suppressor gene in papillary thyroid carcinoma
De-tao Yin1, Wenxun Wu, Mingchuang Li
1Department of Thyroid Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, People's Republic of China. detaoyin@zzu.edu.cn
Abstract:
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.
Insights
Dickkopf homolog 3 (DKK3) gene downregulation in thyroid cancer is linked to promoter methylation. DKK3 acts as a tumor suppressor, with its methylation correlating to increased tumor aggressiveness.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Dickkopf homolog 3 (DKK3) gene expression is reduced in various human cancers, suggesting a tumor suppressor function.
- The specific role and regulation of DKK3 in thyroid cancer remain largely unexamined.
Purpose of the Study:
- To investigate the association between DKK3 promoter methylation and its inactivation in papillary thyroid carcinoma (PTC).
- To explore the relationship between DKK3 expression, promoter methylation, and tumor behaviors in PTC.
Main Methods:
- Utilized methylation-specific PCR and RT-PCR to analyze DKK3 promoter methylation and mRNA expression in PTC tissues and matched normal samples.
- Correlated DKK3 methylation and expression levels with clinicopathological characteristics of PTC.
- Treated PTC cell line TPC-1 with a demethylating agent (5-azaC) to assess functional impact on DKK3 expression.
Main Results:
- DKK3 mRNA expression was significantly lower in PTC tissues (44.9%) compared to normal thyroid tissues (100%).
- DKK3 promoter methylation was detected in 38.8% of PTC samples, contrasting with 0% in normal tissues.
- An inverse correlation was observed between DKK3 promoter methylation and its mRNA expression, as well as between DKK3 expression and aggressive PTC features (high TNM stage, lymph node metastasis).
- DKK3 promoter hypermethylation positively correlated with tumor pathological aggressiveness.
Conclusions:
- DKK3 functions as a potential tumor suppressor gene in thyroid cancer.
- Aberrant promoter methylation is a key mechanism driving DKK3 downregulation in PTC.
- DKK3 methylation may contribute to PTC tumorigenesis and disease progression.
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