Impaired microRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness

Julia Ramírez-Moya,Garcilaso Riesco-Eizaguirre,León Wert-Lamas,Pilar Santisteban

doi:10.1038/s41388-019-0804-8

Abstract

The global downregulation of microRNAs (miRNAs) is emerging as a common hallmark of cancer. However, the mechanisms underlying this phenomenon are not well known. We identified that the oncogenic miR-146b-5p attenuates miRNA biosynthesis by targeting DICER1 and reducing its expression. DICER1 overexpression inhibited all the miR-146b-induced aggressive phenotypes in thyroid cells. Systemic injection of an anti-miR-146b in mice with orthotopic thyroid tumors suppressed tumor growth and recovered DICER1 levels. Notably, DICER1 downregulation promoted proliferation, migration, invasion, and epithelial-mesenchymal transition through miRNA downregulation. Our analysis of The Cancer Genome Atlas revealed a general decrease in DICER1 expression in thyroid cancer that was associated with a worse clinical outcome. Administration of the small-molecule enoxacin to promote DICER1 complex activity reduced tumor aggressiveness both in vitro and in vivo. Overall, our data confirm DICER1 as a tumor suppressor and show that oncogenic miR-146b contributes to its downregulation. Moreover, our results highlight a potential therapeutic application of RNA-based therapies including miRNA inhibitors and restoration of the biogenesis machinery, which may provide treatments for thyroid and other cancers.

Highlights

IntroductionIn thyroid cancer, differentiated PTC and FTC present both up- and downregulated miRNAs, whereas dedifferentiated and aggressive ATC show almost exclusively downregulated miRNAs, with various reports describing 44 downregulated miRNAs and only 6 upregulated miRNAs [12,13,14]
MicoRNAs are short noncoding RNAs that function post-transcriptionally to suppress gene expression through interactions of their seed region with complementary sequences in the 3′-untranslated regions (UTRs) of target messenger RNAs, which affects a Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Thyroid cancer is the most frequent endocrine malignancy and is the most rapidly increasing of all cancers in the United States [5]
In thyroid cancer, differentiated PTC and FTC present both up- and downregulated miRNAs, whereas dedifferentiated and aggressive ATC show almost exclusively downregulated miRNAs, with various reports describing 44 downregulated miRNAs and only 6 upregulated miRNAs [12,13,14]. This suggests that the progression of differentiated thyroid carcinomas to aggressive ATC is characterized by changes in miRNA expression, and that miRNA downregulation might play a role in this transition

Summary

Introduction

In thyroid cancer, differentiated PTC and FTC present both up- and downregulated miRNAs, whereas dedifferentiated and aggressive ATC show almost exclusively downregulated miRNAs, with various reports describing 44 downregulated miRNAs and only 6 upregulated miRNAs [12,13,14]. This suggests that the progression of differentiated thyroid carcinomas to aggressive ATC is characterized by changes in miRNA expression, and that miRNA downregulation might play a role in this transition. The precise role that DICER1 plays in thyroid tumor progression is not clear

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