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Background: MiR-146b has been reported to be overexpressed in papillary thyroid cancer (PTC) tissues and associated with aggressive PTC. MiR-146b is regarded as a relevant diagnostic marker for this type of cancer. MiR-146b-5p has been confirmed to increase cell proliferation by repressing SMAD4. However, detailed functional analysis of another mature form of miR-146b, miR-146b-3p, has not been carried out. This study aimed to identify the differential expression of miR-146b-5p and miR-146b-3p in more aggressive PTC associated with lymph node metastasis, and further elucidate the contribution and mechanism of miR-146b-3p in the process of PTC metastasis. Methods: Expression of miR-146b-5p and miR-146b-3p was assessed in formalin-fixed paraffin-embedded tissue samples from PTC patients, and the relationship with lymph node metastasis was analyzed. A variety of PTC cells, including BHP10-3, BHP10-3SCmice, and K1 cells, were cultured and treated with miR-146b-5p or miR-146b-3p mimics/inhibitors. The cell migration and invasion abilities were characterized by the real-time cell analyzer assay and Transwell™ assay. PTC xenograft models were used to examine the effect of miR-146b-3p on PTC metastatic ability in vivo. Direct downstream targets of miR-146b-3p were analyzed by luciferase reporter assay and Western blotting. The mechanism by which miR-146b-3p affects cell metastasis was further characterized by co-transfection with merlin, the protein product of the NF2 gene. Results: MiR-146b-5p and miR-146b-3p expression was significantly higher in thyroid cancer tissues and cell lines than in normal thyroid tissue and cells. Moreover, expression of miR-146b-5p and miR-146b-3p was further increased in thyroid metastatic nodes than in thyroid cancer. After overexpression of miR-146b-5p or miR-146b-3p in BHP10-3 or K1 cells, PTC migration and invasion were increased. Notably, miR-146b-3p increased cell migration and invasion more obviously than did miR-146b-5p. Overexpression of miR-146b-3p also significantly promoted PTC tumor metastasis in vivo. Luciferase reporter assay results revealed that NF2 is a downstream target of miR-146b-3p in PTC cells, as miR-146b-3p bound directly to the 3' untranslated region of NF2, thus reducing protein levels of NF2. Overexpression of merlin reversed the enhanced aggressive effects of miR-146b-3p. Conclusions: Overexpression of miR-146b-5p and miR-146b-3p is associated with PTC metastasis. MiR-146b-3p enhances cell invasion and metastasis more obviously than miR-146b-5p through the suppression of the NF2 gene. These findings suggest a potential diagnostic and therapeutic value of these miRNAs in PTC metastasis.

Citation

Chunxiao Yu, Li Zhang, Dandan Luo, Fang Yan, Jia Liu, Shanshan Shao, Lifang Zhao, Tong Jin, Jiajun Zhao, Ling Gao. MicroRNA-146b-3p Promotes Cell Metastasis by Directly Targeting NF2 in Human Papillary Thyroid Cancer. Thyroid : official journal of the American Thyroid Association. 2018 Dec;28(12):1627-1641

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PMID: 30244634

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