MicroRNA-146b promotes PI3K/AKT pathway hyperactivation and thyroid cancer progression by targeting PTEN View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-06

AUTHORS

Julia Ramírez-Moya, León Wert-Lamas, Pilar Santisteban

ABSTRACT

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. More... »

PAGES

3369-3383

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41388-017-0088-9

    DOI

    http://dx.doi.org/10.1038/s41388-017-0088-9

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1100512166

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29353884


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