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

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Impaired microRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness.
Oncogene ( IF 6.9 ) Pub Date : 2019-04-09 , DOI: 10.1038/s41388-019-0804-8
Julia Ramírez-Moya _{1,

2} , León Wert-Lamas _{1,

3} , Garcilaso Riesco-Eizaguirre _{1,

2,

3,

4} , Pilar Santisteban _{1,

2}

Affiliation

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.

中文翻译：

DICER1 下调导致的 microRNA 加工受损，使甲状腺癌的侵袭性增加。

microRNAs (miRNAs) 的全球下调正在成为癌症的一个共同标志。然而，这种现象背后的机制尚不清楚。我们发现致癌的 miR-146b-5p 通过靶向 DICER1 并降低其表达来减弱 miRNA 的生物合成。DICER1 过表达抑制了甲状腺细胞中所有 miR-146b 诱导的侵袭性表型。在患有原位甲状腺肿瘤的小鼠中全身注射抗 miR-146b 可抑制肿瘤生长并恢复 DICER1 水平。值得注意的是，DICER1 下调通过 miRNA 下调促进增殖、迁移、侵袭和上皮间质转化。我们对癌症基因组图谱的分析揭示了甲状腺癌中 DICER1 表达的普遍下降，这与较差的临床结果相关。施用小分子依诺沙星以促进 DICER1 复合物活性降低了体外和体内的肿瘤侵袭性。总体而言，我们的数据证实 DICER1 是一种肿瘤抑制因子，并表明致癌 miR-146b 有助于其下调。此外，我们的研究结果突出了基于 RNA 的疗法的潜在治疗应用，包括 miRNA 抑制剂和生物发生机制的恢复，这可能为甲状腺和其他癌症提供治疗。

更新日期：2019-05-16

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