Impaired microRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness.
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-146binduced
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.
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