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

• Published in: Frontiers in immunology 2023, Vol.14, p.1171816
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - genetics; beta Catenin - metabolism; Carcinoma, Papillary - genetics; Carcinoma, Papillary - metabolism; Ligands; Membrane Proteins - metabolism; Mice; Mice, Nude; NK Cell Lectin-Like Receptor Subfamily K - genetics; NK Cell Lectin-Like Receptor Subfamily K - metabolism; Proto-Oncogene Proteins B-raf; Thyroid Cancer, Papillary - genetics; Thyroid Neoplasms - pathology; Up-Regulation; Wnt Signaling Pathway - physiology
• ISSN: 1664-3224
• DOI: 10.3389/fimmu.2023.1171816

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