Faria Márcia, Domingues Rita, Bugalho Maria João, Matos Paulo, Silva Ana Luísa
Serviço de Endocrinologia, Diabetes e Metabolismo, do Centro Hospitalar Universitário de Lisboa Norte-Hospital Santa Maria, 1649-035 Lisboa, Portugal.
BioISI-Biosystems and Integrative Sciences Institute, Faculdade de Ciências da Universidade de Lisboa, 1749-016 Lisboa, Portugal.
Cancers (Basel). 2021 Nov 22;13(22):5861. doi: 10.3390/cancers13225861.
The Sodium/Iodide Symporter (NIS) is responsible for the active transport of iodide into thyroid follicular cells. Differentiated thyroid carcinomas (DTCs) usually preserve the functional expression of NIS, allowing the use of radioactive iodine (RAI) as the treatment of choice for metastatic disease. However, a significant proportion of patients with advanced forms of TC become refractory to RAI therapy and no effective therapeutic alternatives are available. Impaired iodide uptake is mainly caused by the defective functional expression of NIS, and this has been associated with several pathways linked to malignant transformation. MAPK signaling has emerged as one of the main pathways implicated in thyroid tumorigenesis, and its overactivation has been associated with the downregulation of NIS expression. Thus, several strategies have been developed to target the MAPK pathway attempting to increase iodide uptake in refractory DTC. However, MAPK inhibitors have had only partial success in restoring NIS expression and, in most cases, it remained insufficient to allow effective treatment with RAI. In a previous work, we have shown that the activity of the small GTPase RAC1 has a positive impact on TSH-induced NIS expression and iodide uptake in thyroid cells. RAC1 is a downstream effector of NRAS, but not of BRAF. Therefore, we hypothesized that the positive regulation induced by RAC1 on NIS could be a relevant signaling cue in the mechanism underlying the differential response to MEK inhibitors, observed between NRAS- and BRAF-mutant tumors. In the present study, we found that the recovery of NIS expression induced through MAPK pathway inhibition can be enhanced by potentiating RAC1 activity in thyroid cell systems. The negative impact on NIS expression induced by the MAPK-activating alterations, NRAS Q61R and BRAF V600E, was partially reversed by the presence of the MEK 1/2 inhibitors AZD6244 and CH5126766. Notably, the inhibition of RAC1 signaling partially blocked the positive impact of MEK inhibition on NIS expression in NRAS Q61R cells. Conversely, the presence of active RAC1 considerably improved the rescue of NIS expression in BRAF V600E thyroid cells treated with MEK inhibitors. Overall, our data support an important role for RAC1 signaling in enhancing MAPK inhibition in the context of RAI therapy in DTC, opening new opportunities for therapeutic intervention.
钠/碘同向转运体（NIS）负责将碘主动转运至甲状腺滤泡细胞。分化型甲状腺癌（DTC）通常保留NIS的功能性表达，这使得放射性碘（RAI）成为转移性疾病的首选治疗方法。然而，相当一部分晚期甲状腺癌患者对RAI治疗产生耐药，且没有有效的治疗替代方案。碘摄取受损主要是由NIS的功能性表达缺陷引起的，这与几种与恶性转化相关的途径有关。MAPK信号通路已成为参与甲状腺肿瘤发生的主要途径之一，其过度激活与NIS表达下调有关。因此，已经开发了几种靶向MAPK途径的策略，试图增加难治性DTC中的碘摄取。然而，MAPK抑制剂在恢复NIS表达方面仅取得了部分成功，在大多数情况下，这仍不足以允许用RAI进行有效治疗。在之前的一项工作中，我们已经表明小GTPase RAC1的活性对促甲状腺激素诱导的甲状腺细胞中NIS表达和碘摄取有积极影响。RAC1是NRAS的下游效应物，但不是BRAF的下游效应物。因此，我们假设RAC1对NIS的正向调节可能是NRAS和BRAF突变肿瘤之间观察到的对MEK抑制剂差异反应机制中的一个相关信号线索。在本研究中，我们发现在甲状腺细胞系统中增强RAC1活性可以增强通过MAPK途径抑制诱导的NIS表达恢复。MAPK激活改变NRAS Q61R和BRAF V600E对NIS表达的负面影响被MEK 1/2抑制剂AZD6244和CH5126766部分逆转。值得注意的是，抑制RAC1信号通路部分阻断了MEK抑制对NRAS Q61R细胞中NIS表达的正向影响。相反，活性RAC1的存在显著改善了用MEK抑制剂处理的BRAF V600E甲状腺细胞中NIS表达的挽救。总体而言，我们的数据支持RAC1信号通路在DTC的RAI治疗背景下增强MAPK抑制中的重要作用，为治疗干预开辟了新机会。
