Abstract
Mutations in the miRNA enzyme gene DICER1 have been reported in several endocrine malignancies and is associated with the rare tumour-predisposing DICER1 syndrome. DICER1 mutations have been reported in subsets of follicular thyroid carcinoma (FTC), but the role of DICER1 in follicular thyroid tumorigenesis has not been extensively studied. In this study, we investigate the role of DICER1 in 168 follicular thyroid tumours and in an FTC cell line. We found rare DICER1 mutations in paediatric FTC cases and a general DICER1 down-regulation in FTCs visualized both on mRNA and protein level, especially pronounced in Hürthle cell carcinoma (HuCC). The down-regulation was also evident in follicular thyroid adenomas (FTAs), suggesting a potential early step in tumorigenesis. The expression of DICER1 was lower in FTCs of older patients in which TERT promoter mutations are more frequent. In FTCs, DICER1 down-regulation was not caused by gene copy number loss but significantly correlated to expression of the transcription factor GABPA in clinical cases. GABPA was found to bind to the DICER1 promoter and regulate DICER1 expression in vitro, as GABPA depletion in FTC cell lines reduced DICER1 expression. This in turn stimulated cell proliferation and affected the miRNA machinery, evident by altered miRNA expression. To conclude, we show that GABPA directly regulates DICER1 in FTC, acting as a tumour suppressor and displaying down-regulation in clinical samples. We also show reduced expression of DICER1 in benign and malignant follicular thyroid tumours, suggesting a potentially early tumorigenic role of this gene aberrancy.
Highlights
Thyroid cancer is the most common endocrine malignancy and accounts for about 1–3% of all new cases of cancers and occurs predominantly in women (Siegel et al 2018)
The follicular thyroid adenomas (FTAs) and follicular tumour of uncertain malignant potential (FT-UMP) groups included 15 and four Hürthle cell tumours, respectively, whereas the HuCCs were separated from the Follicular thyroid carcinoma (FTC) group
There was no relapse in the FTA group but one relapse in the FT-UMP group
Summary
Thyroid cancer is the most common endocrine malignancy and accounts for about 1–3% of all new cases of cancers and occurs predominantly in women (Siegel et al 2018). The incidence of thyroid cancer has steadily increased for the last few decades, especially since the beginning of the 1990s, but the mortality rate has remained relatively stable (Kitahara & Sosa 2016). The increase is mainly attributable to the increasing incidence of papillary thyroid carcinoma (PTC), but all forms show an increase (Davies & Welch 2014, Carlberg et al 2016, Kitahara & Sosa 2016, Cronin et al 2018). 27:5 for about 10–15% of all thyroid cancers (AschebrookKilfoy et al 2011). FTCs with an oxyphilic phenotype are classified as Hürthle cell carcinomas (HuCC), and these show a worse clinical outcome (Lloyd et al 2017)
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