β-catenin attenuation leads to up-regulation of activating NKG2D ligands and tumor regression in Braf V600E -driven thyroid cancer cells.

Introduction: BRAF ^V600E mutations frequently occur in papillary thyroid cancer (PTC). β-catenin, encoded by CTNNB1 , is a key downstream component of the canonical Wnt signaling pathway and is often overexpressed in PTC. BRAF ^V600E -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 BRAF ^V600E PTC mice following Ctnnb1 ablation (BVE- Ctnnb1 ^null ).
Results: Remarkably, the tumorigenic potential of BVE- Ctnnb1 ^null tumor cells was lost in nude mice. Global gene expression analysis of BVE- Ctnnb1 ^null 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- Ctnnb1 ^null tumor cells. In vitro cytotoxicity assay demonstrated that BVE- Ctnnb1 ^wt tumor cells were resistant to NK cell-mediated cytotoxicity, whereas BVE- Ctnnb1 ^null tumor cells were sensitive to NK cell-mediated killing. Furthermore, the overexpression of any one of these NKG2D ligands in the BVE- Ctnnb1 ^wt 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 BRAF -mutant thyroid cancer by not only inhibiting tumor growth but also enhancing host immune surveillance.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Zou, Al-Yahya, Al-Alwan, BinEssa, Khabar, Almohanna, Assiri, Altaweel, Qattan, Meyer, Alzahrani and Shi.)