Epigenetic silencing of the tumor suppressor TIMP-3 gene in upstream CpG islands in thyroid neoplasms: a cross-sectional study with systematic review.

BACKGROUND

Despite advances in understanding thyroid cancer pathogenesis, the specific epigenetic mechanisms driving malignant transformation remain incompletely characterized. While genetic variations have been well documented, the role of DNA methylation, particularly involving tumor suppressor genes, represents a critical knowledge gap. This resaerch aimed to evaluate the methylation status of the tissue inhibitor of metalloproteinase 3 (TIMP-3) promoter across 15 CpG sites in papillary and follicular thyroid carcinomas (PTC and FTC) compared to benign thyroid lesions, and to contextualize these findings through a review of previous studies on TIMP-3 promoter methylation.

METHODS

Thyroid specimens from 64 patients were analyzed, including 28 with PTC, 9 with FTC, and 27 with benign thyroid nodules. TIMP-3 expression was evaluated by qRT-PCR, and promoter methylation status was assessed using bisulfite sequencing PCR. For systematic review, a comprehensive literature search was conducted using specific terms related to "thyroid neoplasms," "DNA methylation," and "TIMP-3" across Web of Science, Scopus, and PubMed/MEDLINE databases.

RESULTS

TIMP-3 mRNA levels were decreased in FTC and PTC tumor tissues compared to adjacent normal thyroid tissue (P = 0.02 and P = 0.03). FTC tissues showed reduced TIMP-3 expression compared to benign nodule lesions (P = 0.04). The highest methylation in PTC samples occurred at the 8th, 6th, and 5th CpG sites, while in FTC samples, it was at the 15th, 9th, 2nd, 12th, and 14th CpG sites. Significant hypermethylation was observed in the TIMP-3 promoter in both tumor tissues in comparison to adjacent normal thyroid tissue and benign nodule lesions (P < 0.05). There was a significant correlation between expression and total hypermethylation status of PTC and FTC tissues (P < 0.05). A literature search identified five relevant studies.

CONCLUSION

Changes in the methylation pattern of the TIMP-3 promoter could help distinguish between benign and malignant thyroid nodules. These changes could be explored as targets for demethylation interventions, potentially opening new avenues for treatments aimed at restoring normal methylation patterns and influencing thyroid nodule behavior.