β-catenin 减弱导致 Braf(V600E) 驱动的甲状腺癌细胞中活化型 NKG2D 配体上调及肿瘤消退

In the present study, we investigated the tumorigenicity of thyroid cancer cells derived from BRAF V600E PTC mice following Ctnnb1 ablation (BVE- Ctnnb1 null ).

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.

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.