β-catenin attenuation leads to up-regulation of activating NKG2D ligands and tumor regression in -driven thyroid cancer cells.

[INTRODUCTION] mutations frequently occur in papillary thyroid cancer (PTC). β-catenin, encoded by , is a key downstream component of the canonical Wnt signaling pathway and is often overexpressed in PTC. -driven PTC tumors rely on Wnt/β-catenin signaling to sustain growth and progression.

[METHODS] In the present study, we investigated the tumorigenicity of thyroid cancer cells derived from PTC mice following ablation (BVE-).

[RESULTS] Remarkably, the tumorigenic potential of BVE- tumor cells was lost in nude mice. Global gene expression analysis of BVE- tumor cells showed up-regulation of NKG2D receptor activating ligands (H60a, H60b, H60c, Raet1a, Raet1b, Raet1c, Raet1d, Raet1e, and Ulbp1) and down-regulation of inhibitory MHC class I molecules H-2L and H-2K2 in BVE- tumor cells. cytotoxicity assay demonstrated that BVE- tumor cells were resistant to NK cell-mediated cytotoxicity, whereas BVE- tumor cells were sensitive to NK cell-mediated killing. Furthermore, the overexpression of any one of these NKG2D ligands in the BVE- cell line resulted in a significant reduction of tumor growth in nude mice.

[CONCLUSIONS] Our results indicate that active β-catenin signaling inhibits NK cell-mediated immune responses against thyroid cancer cells. Targeting the β-catenin signaling pathway may have significant therapeutic benefits for -mutant thyroid cancer by not only inhibiting tumor growth but also enhancing host immune surveillance.