Effect of miR-146b silencing in thyroid cancer

Abstract

MicroRNAs (miRNAs) are small endogenous noncoding RNAs that regulate the expression of target mRNAs post-transcriptionally, and that are commonly deregulated in cancer. In thyroid cancer, the most frequent type of endocrine cancer, miR-146b is the most highly expressed miRNA in papillary (the most prevalent histotype and with good prognosis) and anaplastic thyroid cancer (less frequent but the most aggressive), and is associated with aggressive clinic-pathological characteristics and with BRAF mutation. BRAFV600E mutation is the most prevalent genetic alteration in thyroid cancer (50% of cases of papillary and 10% of anaplastic) associated with poor prognosis. The activation of BRAFV600E induces the deregulation of miRNA that contribute to oncogenesis and progression. Indeed, in vitro, BRAFV600E leads to loss of thyroid differentiation in a loop with miR-146b to inhibit NIS protein responsible for iodine trapping in follicular cells, and whose reduction is associated with radioiodine refractoriness in aggressive cancer. Recent studies and clinical-trials are investigating the potential and applicability of miRNA silencing in various types of cancer. Thus, this project aims to understand the role of miR-146b in aggressive thyroid cancer model using gene editing methodology via CRISPR/Cas9n to silence MIR146b gene. For that, in vitro assays (proliferation, viability, invasion and cell migration) and in vivo modeling in mice will be used after the construction of anaplastic thyroid cancer cell line with miR-146b silencing, and we expect this study to contribute to a better understanding of aggressive thyroid cancer biology. (AU)