Background: Differentiated thyroid cancer (DTC) is commonly treated with radioactive iodine (RAI), but resistance to RAI remains a significant clinical challenge. The molecular mechanisms driving dedifferentiation and RAI refractoriness, particularly in BRAFV600E-mutated tumors, are not fully understood. Methods: RNA sequencing was conducted on BRAFV600E-mutated DTC and RAIR-DTC tissue samples to identify differentially expressed genes. Gadd45B was identified as significantly downregulated in RAIR-DTC. Functional studies including overexpression and knockdown experiments were performed in thyroid cancer cell lines and xenograft models. Downstream targets, including MAP3K4 and MYCBP, were evaluated through co-immunoprecipitation, luciferase assays, and Western blot. The therapeutic efficacy of recombinant Gadd45B protein in combination with BRAFV600Eand TERT inhibitors was assessed in patient-derived xenograft (PDX) models. Results: Gadd45B overexpression suppressed MAPK pathway activity by interacting with MAP3K4 and downregulated c-MYC stability through competition with MYCBP. These interactions enhanced the expression of iodine-metabolism genes (NIS, TPO, Tg), increased RAI uptake, and reversed tumor dedifferentiation. In vivo, Gadd45B restoration reduced tumor burden and improved RAI uptake. Combined treatment with Gadd45B protein, PLX4720, and BIBR1532 produced synergistic therapeutic effects in PDX models. Conclusions: Gadd45B plays a pivotal role in regulating the differentiation status and RAI sensitivity of BRAFV600E-mutated thyroid cancer. These findings identify Gadd45B as a promising therapeutic target for restoring RAI responsiveness in RAIR-DTC patients.
背景：分化型甲状腺癌（DTC）通常采用放射性碘（RAI）治疗，但对RAI的耐药性仍是临床面临的重要挑战。驱动肿瘤去分化及RAI抵抗的分子机制，尤其在BRAFV600E突变肿瘤中，尚未完全阐明。方法：对BRAFV600E突变的DTC及RAI耐药性DTC（RAIR-DTC）组织样本进行RNA测序，以鉴定差异表达基因。研究发现Gadd45B在RAIR-DTC中显著下调。在甲状腺癌细胞系及异种移植模型中进行了包括过表达和敲低实验在内的功能研究。通过免疫共沉淀、荧光素酶报告实验及Western blot评估了下游靶点（包括MAP3K4和MYCBP）。在患者来源异种移植（PDX）模型中评估了重组Gadd45B蛋白联合BRAFV600E及TERT抑制剂的治疗效果。结果：Gadd45B过表达通过与MAP3K4相互作用抑制MAPK通路活性，并通过竞争MYCBP下调c-MYC稳定性。这些相互作用增强了碘代谢相关基因（NIS、TPO、Tg）的表达，提高了RAI摄取能力，并逆转了肿瘤去分化状态。在体内实验中，恢复Gadd45B表达降低了肿瘤负荷并改善了RAI摄取。在PDX模型中，Gadd45B蛋白与PLX4720、BIBR1532的联合治疗产生了协同治疗效果。结论：Gadd45B在调控BRAFV600E突变甲状腺癌的分化状态及RAI敏感性中发挥关键作用。这些发现表明Gadd45B是恢复RAIR-DTC患者RAI应答潜力的重要治疗靶点。
肿瘤(癌症)患者之家