Abstract
MicroRNA-497 (miR-497) has been reported to be a tumor-suppressive miRNA in thyroid cancer (TC), yet the mechanism is not clearly defined. In this study, we aim to determine the mechanism by which miR-497-3p affects the progression of TC. After characterization of low miR-497-3p expression pattern in TC and normal tissues, we assessed the correlation between miR-497-3p expression and clinicopathological features of TC patients. Its low expression shared associations with advanced tumor stage and lymph node metastasis. ChIP and methylation-specific PCR provided data showing that downregulation of miR-497-3p in TC tissues was induced by DNA methyltransferase-mediated hypermethylation. By performing dual-luciferase reporter assay, we identified that miR-497-3p targeted PAK1 while PAK1 could inhibit β-catenin expression. Through this mechanism, miR-497-3p exerted the anti-proliferative, anti-invasive, pro-apoptotic, and anti-tumorigenic effects on TC cells on the strength of the results from gain-of-function and rescue experiments. This study suggested that hypermethylation of miR-497-3p resulted in upregulation of β-catenin dependent on PAK1 and contributed to cancer progression in TC, which highlighted one of miR-mediated tumorigenic mechanism.
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Yuxia Fan conceived and together with Hao Yan and Qingling Yuan designed the study. Xin Fan and Xiaoming Wang were involved in data collection. Zheng Liu and Xiubo Lu performed the statistical analysis and preparation of figures. Jie Xie and Yang Yang drafted the paper. All authors read and approved the final manuscript.
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The study protocol was granted by the Ethics Committee of The First Affiliated Hospital of Zhengzhou University. All participants provided signed informed documentation. The animal experimentation was operated with approval of the Animal Ethics Committee of The First Affiliated Hospital of Zhengzhou University.
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Fan, Y., Fan, X., Yan, H. et al. Hypermethylation of microRNA-497-3p contributes to progression of thyroid cancer through activation of PAK1/β-catenin. Cell Biol Toxicol 39, 1979–1994 (2023). https://doi.org/10.1007/s10565-021-09682-1
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DOI: https://doi.org/10.1007/s10565-021-09682-1