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Yin D.-T.,Zhengzhou University | Yin D.-T.,Key Discipline Laboratory of Clinical Medicine Henan | Wu W.,Zhengzhou University | Li M.,Zhengzhou University | And 9 more authors.
Endocrine-Related Cancer

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. © 2013 Society for Endocrinology Published by Bioscientifica Ltd. Source

Yin D.-T.,Zhengzhou University | Yin D.-T.,Key Discipline Laboratory of Clinical Medicine Henan | Xu J.,Zhengzhou University | Xu J.,Key Discipline Laboratory of Clinical Medicine Henan | And 10 more authors.

Background: Some studies showed an association of coiled-coil domain-containing (CCDC) genes with cancers. Our previous limited data specifically suggested a possible pathogenic role of CCDC67 in papillary thyroid cancer (PTC), but this has not been firmly established. The present study was to further investigate and establish this role of CCDC67 in PTC. Results: The expression of CCDC67, both at mRNA and protein levels, was sharply down-regulated in PTC compared with normal thyroid tissues. Lower CCDC67 expression was significantly associated with aggressive tumor behaviors, such as advanced tumor stages and lymph node metastasis, as well as BRAF mutation. Introduced expression of CCDC67 in TPC-1 cells robustly inhibited cell proliferation, colony formation and migration, induced G1 phase cell cycle arrest, and increased cell apoptosis. Methods: Primary PTC tumors and matched normal thyroid tissues were obtained from 200 unselected patients at the initial surgery for detection of CCDC67 mRNA and protein by RT-PCR and Western blotting analyses, respectively. Genomic DNA sequencing was performed to detect BRAF mutation in PTC tumors. Clinicopathological data were retrospectively reviewed for correlation analyses. PTC cell line TPC-1 with stable transfection of CCDC67 was used to investigate the functions of CCDC67. Conclusions: This large study demonstrates down-regulation of CCDC67 in PTC, an inverse relationship between CCDC67 expression and PTC aggressiveness and BRAF mutation, and a robust inhibitory effect of CCDC67 on PTC cellular activities. These results are consistent with CCDC67 being a novel and impaired tumor suppressor gene in PTC, providing important prognostic and therapeutic implications for this cancer. Source

Yin D.-T.,Zhengzhou University | Yin D.-T.,Key Discipline Laboratory of Clinical Medicine Henan | Yu K.,Zhengzhou University | Yu K.,Key Discipline Laboratory of Clinical Medicine Henan | And 13 more authors.
Clinical Endocrinology

Background: The prognostic value of the telomerase reverse transcriptase (TERT) promoter mutation, resulting in poor clinical outcomes of papillary thyroid carcinoma (PTC), has been generally confirmed. To data, there is no high-level evidence approving the association of TERT promoter mutation and aggressive clinical behaviours in PTC. To systematically evaluate it, a systematic review and meta-analysis of the published literatures were carried out. Methods: We conducted a systematic search in PubMed, EMBASE, OVID and Web of Science databases for relevant studies. We selected all the studies that reported clinicopathological features of PTC patients with information available on TERT promoter mutation status. Individual study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, as were Mantel–Haenszel pooled odds ratios for the combined studies. Results: Eight eligible trials involved 2035 patients were included in the analysis. The average prevalence of the TERT promoter mutation was 10·32%. Compared with the wild-type TERT promoter gene, the TERT promoter mutation was associated with male gender, lymph node metastasis, extrathyroidal extension, distant metastasis, advanced TNM stage III/IV, poor clinical outcome (persistence or recurrence) and mortality. The associations were generally consistent across the different study populations. Conclusions: Thus, our findings from this large meta-analysis definitively demonstrate that TERT promoter mutation-positive PTC is more likely to manifest with aggressive clinicopathological characteristics. In appropriate clinical settings, testing for the TERT promoter mutation is likely to be useful in assisting the risk stratification and management of PTC. © 2016 John Wiley & Sons Ltd Source

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