MicroRNA-۵۰۶ as a tumor suppressor in anaplastic thyroid carcinoma by regulation of WNT and NOTCH signaling pathways

Objective(s): Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid tumor type that has a poor prognosis due to its high therapeutic resistance. Since ATC accounts for half of thyroid cancer-related deaths, it is required to introduce novel therapeutic targets to increase survival in ATC patients. WNT and NOTCH signaling pathways are the pivotal regulators of cell proliferation and migration that can be regulated by microRNAs. We assessed the role of miR-۵۰۶ in the regulation of cell migration, apoptosis, and drug resistance via NOTCH and WNT pathways in ATC cells.Materials and Methods: The levels of miR-۵۰۶ expressions were assessed in ATC cells and tissues. The levels of NOTCH, WNT, and EMT-related gene expressions were also assessed in miR-۵۰۶ ectopic expressed cells compared with controls. Cell migration and drug resistance were also evaluated to assess the role of miR-۵۰۶ in the regulation of ATC aggressiveness. Results: There were significant miR-۵۰۶ down-regulations in ATC cells and clinical samples compared with normal cells and margins. MiR-۵۰۶ suppressed NOTCH and WNT signaling pathways through LEF۱, DVL, FZD۱, HEY۲, HES۵, and HEY۲ down-regulations, and APC and GSK۳b up-regulations. MiR-۵۰۶ significantly inhibited ATC cell migration and EMT (P=۰.۰۲۸). Moreover, miR-۵۰۶ significantly increased Cisplatin (P=۰.۰۰۴), Paclitaxel (P<۰.۰۰۰۱), and Doxorubicin (P=۰.۰۰۱۴) sensitivities in ATC cells. Conclusion: MiR-۵۰۶ regulated EMT, cell migration, and chemoresistance through regulation of WNT and NOTCH signaling pathways in ATC cells. Therefore, after confirmation with animal studies, it can be introduced as an efficient novel therapeutic factor for ATC tumors.

Keywords:

Anaplastic thyroid - carcinoma , Chemo resistance , EMT , miR-۵۰۶ , NOTCH , WNT