MicroRNA-146a targets PRKCE to modulate papillary thyroid tumor development

MicroRNAs are single-stranded noncoding RNAs composed of approximately 22 nucleotides that suppress gene expression by selectively binding via base-pairing to the complementary 3-untranslated region (3-UTR) of messenger RNA transcripts. Protein kinase C epsilon (PKC epsilon) is an important modulating member of the transducing Ras/Raf-1 signal pathway; a computational search revealed miR-146a putatively binds to the 3'-UTR of the PRKCE gene, and thus decreasing PKC epsilon expression. Moreover, PKC epsilon inhibits mitochondrial apoptosis and is associated with the Bcl family. However, it has been previously reported that miR-146a expression in papillary thyroid carcinoma (PTC) is slightly elevated. Thus, we hypothesized that because miR-146a expression depends on nuclear factor kappaB (NF-B) activation and NF-B expression is elevated in PTC, miR-146a is potentially upregulated in PTC via negative feedback of NF-B, and thus suppressing PKC epsilon expression. In our study, we investigated whether overexpression of miR-146a, a tumor-suppressing-miR, in PTC cells decreases cell survival and induces apoptosis. Luciferase reporter assay analysis confirmed the direct binding of miR-146a and PRKCE 3-UTR. Specific overexpression of exogenous miR-146a significantly decreased PKC epsilon levels in PTC cell line NPA-187 and increased apoptosis. Additionally, using stably expressing miR-146a thyroid carcinoma cells to establish subcutaneous tumors, the tumor growth exhibited significant inhibition. Our study confirmed the tumor-suppressing role of miR-146a in thyroid carcinoma cells and contributes to the knowledge regarding modulation of Ras/Raf-1 signal transduction and apoptosis via PKC epsilon targeted by miR-146a in PTC; moreover, our findings confirmed that miR-146a is involved in the feedback system of the classical NF-B signal pathway in PTC.