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.

Neogenin has been documented as playing an important role in cancer development. Although an elevated expression of neogenin has been detected in human breast cancer, the role of neogenin in breast cancer cells is not clearly understood. In the present study, we investigated neogenin in breast cancer cell proliferation, migration and apoptosis. We found that neogenin overexpression markedly reduced the proliferation and migration of breast cancer cells (P<0.05). Neogenin overexpression resulted in a reduction in the apoptosis rate. Inhibition of neogenin expression by neogenin siRNA dramatically promoted the proliferation and migration of breast cancer cells, whereas it inhibited cell apoptosis. Furthermore, we found that BMP-2-induced phosphorylation of Smad1/5/8 which was inhibited by neogenin overexpression. The present study demonstrates that neogenin may be a tumor suppressor in breast cancer. Neogenin may serve as a potential diagnostic marker and therapeutic target for breast cancer.

Circular RNAs (circRNAs) have been found to be associated with the development and progression of cancers including papillary thyroid carcinoma (PTC). Circ_LDLR has been reported to be highly expressed in PTC, but its underlying mechanism of action has not been fully elucidated. This study aimed to investigate the role of circ_LDLR in PTC. The expression of circ_LDLR, miR‐1294 and high mobility group box (HMGB) 3 was detected by quantitative real‐time polymerase chain reaction (qRT‐PCR). CCK‐8 assay and transwell assays were employed to value cell viability, invasion and migration abilities. Western blot assay was to detect HMGB3 protein expression. Luciferase reporter gene and pull down assay were used to validate the interaction between miR‐1294 and HMGB3 or circ_LDLR. Circ_LDLR showed high expression levels in PTC tissues and cells and knockdown of it inhibited the growth, invasion, and migration of PTC cells. In addition, miR‐1294 was considered as a downstream target of circ_LDLR, and inhibition of miR‐1294 partially reversed the inhibitory effects of circ_LDLR knockdown on PTC cells growth, invasion, and migration. More importantly, HMGB3 was identified as a downstream target of miR‐1294. Our findings suggest circ_LDLR may plays a promoting role in PTC by downregulating miR‐1294 and upregulating HMGB3 expression. Therefore, circ_LDLR may serve as a valuable prognostic biomarker and therapeutic target for PTC.