Endocrine Abstracts

Objectives: Papillary thyroid carcinoma (PTC) exhibits aberrant expression of retinoic acid receptor β (RARβ), a retinoic acid-inducible transcription factor, essential for cellular growth and development. The mechanisms leading to decreased RARβ expression in tumors are unknown. We hypothesized that changes in expression of RARB, a gene encoding for RARβ, result from aberrant expression of microRNAs. We elucidated the miRNome of normal thyroid and PTC by microarray and next-generation sequencing experiments (NGS) and identified microRNAs highly upregulated in cancer. The list included miR-146a and miR-146b, putative regulators of RARB.

Aim of the study: Aim of the study was to analyze the action of miR-146a and miR-146b on RARβ expression in PTC and its role in development and progression of cancer.

Methods and results: NGS and real-time PCR analysis performed in 30 PTC and match-control tissue samples recognized miR-146a and miR-146b as highly upregulated in PTC. In silico analysis identified RARB as a target for both microRNAs. Q13-PCR analysis of RARB expression showed its downregulation by 65% (P=0.00001) in PTC. Direct interaction between miRNAs and RARB was tested by luciferase assay using a reporter vector, containing RARB 3′UTR cloned downstream of luciferase gene. MicroRNA-146a caused a 37% (P=0.00001) and microRNA-146b a 15% (P=0.0001) reduction of luciferase expression. Impact of miR-146a and miR-146b on RARB was further confirmed in cell line by showing a 28% (P=0.002) and 27% (P=0.006) decrease of endogenous RARB expression respectively.

Conclusion: This is the first study showing microRNA-dependent regulation of RARB expression. Lowered levels of RARB, underlying tumorigenic changes in thyroid gland, may be a result of upregulation of miR-146a and miR-146b observed in PTC. Since disturbances in microRNA expression are reversal, modulating the expression of miR-146a and miR-146b can facilitate future gene therapies in cancers that are resistant to retinoic acid treatment.