Endocrine Abstracts

Thyroid cancer derived from follicular cells is the most frequently endocrine malignancy with an increasing rate of incidence. The identification of new molecules involved in the pathogenesis of these tumors is necessary in order to use it as a novel targets for a better diagnostic and therapy. Recently, the RNA networks emerge as fundamental in the control of gene expression, achieving a strong interest the microRNAs (miRNAs). Our RNA-Seq study together with the analysis of The Cancer Genome Atlas (TCGA) identified novel RNA regulatory mechanism in papillary thyroid carcinomas. We show that miRNA dysregulation involves not only individual changes in the expression of miRNAs, but also disruption of the biogenesis machinery and/or modifications of miRNA sequences by RNA editing. We explored the role of the oncogenic miR-146b, the most upregulated miRNA in thyroid cancer, identifying novel targets that help explain miR-146b-induced cell aggressiveness. Among them, DICER1, the enzyme involved in miRNA biogenesis, is downregulated in thyroid tumor cells overexpressing miR-146b. The decrease in DICER1 levels was associated with a worse clinical outcome of thyroid tumors. Restoration of DICER1 by different treatment reduced tumor aggressiveness both in vitro and in vivo. Currently, RNA editing is getting great relevance in cancer biology. Thus, we investigated the role of adenosine-to-inosine (A-to-I) RNA editing, a process governed by the enzyme ADAR1. We demonstrate that ADAR1 induces thyroid tumorigenesis by a mechanism dependent on the over-editing of the tumor-suppressor miR-200b, impairing its ability to inhibit the epithelial mesenchymal transition factor ZEB1. Altogether our results highlight potential therapeutic approaches based on miRNA inhibition, restoring global miRNA levels via the DICER1 pathway, and suppressing RNA editing, providing a basis for new thyroid cancer treatments.