BRAF^V600E Mutation-Responsive miRNA-222-3p Promotes Metastasis of Papillary Thyroid Cancer Cells via Snail-Induced EMT

BRAF mutation accounts for 50% of the PTC (papillary thyroid carcinoma) and is closely associated with high-risk clinicopathological characteristics. Increasing evidence implied that dysregulation of miRNA participated in carcinogenesis and progression of cancer. Clinical data showed the significant up-regulation of miR-222-3p in PTC; however, the role of miR-222-3p and possible relationship with BRAF mutation remained unclear. Here, we identified significant up-regulation of miR-222-3p in PTC tissues harboring BRAF^V600E mutation compared with BRAF wild type (BRAF^WT ) from collected PTC clinical samples. External validation performed with The Cancer Genome Atlas (TCGA) databases was consistent with the above result. Exogenous expression of BRAF^V600E oncoprotein increased the expression of miR-222-3p in B-CPAP and TPC-1 cells. The treatment of BRAF^V600E and MEK inhibitor, PLX4720 and PD0325901, decreased the expression of miR-222-3p in B-CPAP but not in TPC-1. Inhibition of miR-222-3p significantly suppressed the migration of B-CPAP and induced a mesenchymal-epithelial transition (MET) phenotype via the Snail transcription factor. Immunohistochemistry (IHC) analysis demonstrated the up-regulation of Snail correlated with lymph node metastasis and BRAF^V600E mutation in PTC. Besides, in situ hybridization (ISH) and IHC analysis of PTC clinical samples confirmed the correlation between the expression of miR-222-3p and Snail. These results showed miR-222-3p conduced more aggressive clinical manifestation of PTC by promoting Snail-induced EMT.