Recent studies have shown that miR-146b is the most upregulated microRNA in thyroid cancer and has a central role in cancer progression through mechanisms that remain largely unidentified. As phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a fundamental oncogenic driver in many thyroid cancers, we explored a potential role for miR-146b and its target genes in PI3K/AKT activation. Among the predicted target genes of miR-146b, we found the tumor-suppressor phosphatase and tensin homolog (PTEN). Constitutive overexpression of miR-146b in thyroid epithelial cell lines significantly decreased PTEN mRNA and protein levels by direct binding to its 3'-UTR. This was accompanied by PI3K/AKT hyperactivation, leading to the exclusion of FOXO1 and p27 from the nucleus and a corresponding increase in cellular proliferation. Moreover, miR-146b overexpression led to protection from apoptosis and an increased migration and invasion potential, regulating genes involved in epithelial-mesenchymal transition. Notably, with the single exception of E-cadherin expression, all of these outcomes could be reversed by PTEN coexpression. Further analysis showed that miR-146b directly inhibits E-cadherin expression through binding to its 3'-UTR. Interestingly, miR-146b inhibition in human thyroid tumor xenografts, using a synthetic and clinically amenable molecule, blocked tumor growth when delivered intratumorally. Importantly, this inhibition increased PTEN protein levels. In conclusion, our data define a novel mechanism of PI3K/AKT hyperactivation and outline a regulatory role for miR-146b in suppressing PTEN expression, a frequent observation in thyroid cancer. Both events are related to a more aggressive tumoral phenotype. Targeting miR-146b therefore represents a promising therapeutic strategy for the treatment of this disease.

中文翻译：

---

MicroRNA-146b通过靶向PTEN促进PI3K / AKT途径过度活化和甲状腺癌进展。

最近的研究表明，miR-146b是甲状腺癌中最上调的microRNA，并且在很大程度上尚不清楚的机制下，在癌症进展中具有重要作用。由于磷酸肌醇3激酶/蛋白激酶B（PI3K / AKT）信号是许多甲状腺癌的基本致癌驱动因素，因此我们探索了miR-146b及其靶基因在PI3K / AKT激活中的潜在作用。在miR-146b的预测靶基因中，我们发现了肿瘤抑制磷酸酶和张力蛋白同源物（PTEN）。通过直接与其3'-UTR结合，miR-146b在甲状腺上皮细胞系中的组成性过表达显着降低了PTEN mRNA和蛋白质水平。伴随有PI3K / AKT过度活化，导致FOXO1和p27从细胞核中排除，并相应地增加了细胞增殖。而且，miR-146b的过表达导致细胞免受凋亡保护，并具有增加的迁移和侵袭潜能，从而调节参与上皮-间质转化的基因。值得注意的是，除了E-cadherin表达外，所有这些结果都可以通过PTEN共表达逆转。进一步的分析表明，miR-146b通过与其3'-UTR结合直接抑制E-cadherin的表达。有趣的是，使用合成的和临床上可接受的分子抑制人甲状腺肿瘤异种移植物中的miR-146b可以在肿瘤内递送时阻止肿瘤的生长。重要的是，这种抑制作用增加了PTEN蛋白水平。总之，我们的数据定义了PI3K / AKT过度激活的新机制，并概述了miR-146b在抑制PTEN表达中的调节作用，这在甲状腺癌中经常观察到。这两个事件都与更具侵略性的肿瘤表型有关。因此，靶向miR-146b代表了一种有前途的治疗策略。