BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). β-Catenin ( Ctnnb1 ) is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. BRAF V600E-driven tumors have been speculated to rely on Wnt/β-catenin signaling to sustain its growth, although many details remain to be elucidated. In this study, we investigated the role of β-catenin in BrafV600E -driven thyroid cancer in a transgenic mouse model. In Braf V600E mice with wild-type (WT) Ctnnb1 (BVE-Ctnnb1WT or BVE), overexpression of β-catenin was observed in thyroid tumors. In Braf V600E mice with Ctnnb1 knockout (BVE-Ctnnb1null), thyroid tumor growth was slowed with significant reduction in papillary architecture. This was associated with increased expression of genes involved in thyroid hormone synthesis, elevated 124iodine uptake, and serum T4. The survival of BVE-Ctnnb1null mice was increased by more than 50% during 14-month observation. Mechanistically, downregulation of MAPK, PI3K/Akt, and TGFβ pathways and loss of epithelial–mesenchymal transition (EMT) were demonstrated in the BVE-Ctnnb1null tumors. Treatment with dual β-catenin/KDM4A inhibitor PKF118–310 dramatically improved the sensitivity of BVE-Ctnnb1WT tumor cells to BRAFV600E inhibitor PLX4720, resulting in significant growth arrest and apoptosis in vitro , and tumor regression and differentiation in vivo . These findings indicate that β-catenin signaling plays an important role in thyroid cancer growth and resistance to BRAFV600E inhibitors. Simultaneously targeting both Wnt/β-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAFV600E inhibitor-resistant and/or radioiodine-refractory thyroid cancer.

中文翻译：

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{beta}-连环蛋白衰减抑制 BRAFV600E 驱动的甲状腺癌动物模型中的肿瘤生长并促进分化

BRAFV600E 突变是甲状腺乳头状癌 (PTC) 中最常见的基因改变。β-连环蛋白 (Ctnnb1) 是经典 Wnt 信号通路的关键下游成分，并且经常在 PTC 中过表达。据推测，BRAF V600E 驱动的肿瘤依赖 Wnt/β-catenin 信号传导来维持其生长，尽管许多细节仍有待阐明。在这项研究中，我们在转基因小鼠模型中研究了 β-连环蛋白在 BrafV600E 驱动的甲状腺癌中的作用。在具有野生型 (WT) Ctnnb1 (BVE-Ctnnb1WT 或 BVE) 的 Braf V600E 小鼠中，在甲状腺肿瘤中观察到 β-连环蛋白的过表达。在具有 Ctnnb1 敲除 (BVE-Ctnnb1null) 的 Braf V600E 小鼠中，甲状腺肿瘤生长减慢，乳头结构显着减少。这与参与甲状腺激素合成的基因表达增加有关，124碘摄取升高，血清T4升高。在 14 个月的观察期间，BVE-Ctnnb1null 小鼠的存活率增加了 50% 以上。从机制上讲，在 BVE-Ctnnb1null 肿瘤中证实了 MAPK、PI3K/Akt 和 TGFβ 通路的下调和上皮-间质转化 (EMT) 的丧失。用双重 β-连环蛋白/KDM4A 抑制剂 PKF118-310 治疗显着提高了 BVE-Ctnnb1WT 肿瘤细胞对 BRAFV600E 抑制剂 PLX4720 的敏感性，导致体外显着生长停滞和细胞凋亡，以及体内肿瘤消退和分化。这些发现表明，β-连环蛋白信号在甲状腺癌生长和对 BRAFV600E 抑制剂的抗性中起重要作用。