β-catenin attenuation leads to up-regulation of activating NKG2D ligands and tumor regression in BrafV600E-driven thyroid cancer cells

Frontiers in Immunology

Immunology

Brian F. Meyer¹  Falah Almohanna²  Abdullah M. Assiri²  Ali S. Alzahrani³  Suhad Al-Yahya⁴  Khalid S. A. Khabar⁴  Minjing Zou⁵  Yufei Shi⁵  Huda A. BinEssa⁵  Amal Qattan⁵  Monther Al-Alwan⁶  Abdulmohsen Altaweel⁷ 

[1] Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;Department of Molecular Biomedicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;Department of Stem Cell & Tissue Re-engineering, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia and College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia;Mawhiba, King Abdulaziz and His Companions Foundation for Giftedness and Creativity, Riyadh, Saudi Arabia;

关键词: β-catenin;    CTNNB1;    BRAF;    NKG2D ligands;    NK cells;    thyroid cancer;   

DOI  :  10.3389/fimmu.2023.1171816

 received in 2023-02-22, accepted in 2023-06-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionBRAFV600E 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. BRAFV600E-driven PTC tumors rely on Wnt/β-catenin signaling to sustain growth and progression.MethodsIn the present study, we investigated the tumorigenicity of thyroid cancer cells derived from BRAFV600E PTC mice following Ctnnb1 ablation (BVE-Ctnnb1null).ResultsRemarkably, the tumorigenic potential of BVE-Ctnnb1null tumor cells was lost in nude mice. Global gene expression analysis of BVE-Ctnnb1null 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-Ctnnb1null tumor cells. In vitro cytotoxicity assay demonstrated that BVE-Ctnnb1wt tumor cells were resistant to NK cell-mediated cytotoxicity, whereas BVE-Ctnnb1null tumor cells were sensitive to NK cell-mediated killing. Furthermore, the overexpression of any one of these NKG2D ligands in the BVE-Ctnnb1wt cell line resulted in a significant reduction of tumor growth in nude mice. ConclusionsOur 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.

【 授权许可】

Unknown   
Copyright © 2023 Zou, Al-Yahya, Al-Alwan, BinEssa, Khabar, Almohanna, Assiri, Altaweel, Qattan, Meyer, Alzahrani and Shi