Introduction

AUTHOR=Zou Minjing , Al-Yahya Suhad , Al-Alwan Monther , BinEssa Huda A. , Khabar Khalid S. A. , Almohanna Falah , Assiri Abdullah M. , Altaweel Abdulmohsen , Qattan Amal , Meyer Brian F. , Alzahrani Ali S. , Shi Yufei TITLE=β-catenin attenuation leads to up-regulation of activating NKG2D ligands and tumor regression in BrafV600E-driven thyroid cancer cells JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1171816 DOI=10.3389/fimmu.2023.1171816 ISSN=1664-3224 ABSTRACT=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.