More Candy C B, Bueno Ana Carolina, Rojas César A O, Stecchini Mônica F, Ramalho Fernando S, Brandalise Silvia R, Cardinalli Izilda A, Yunes José Andres, Junqueira Thais, Scrideli Carlos A, Castro Margaret, Antonini Sonir R R
Department of Pediatrics, Ribeirao Preto Medical School - University of Sao Paulo, Ribeirao Preto, Brazil.
Hematology Division, LIM31, Medical School, University of Sao Paulo, Sao Paulo, Brazil.
J Clin Endocrinol Metab. 2025 Jan 10. doi: 10.1210/clinem/dgaf013.
Adrenocortical cancer (ACC) is rare and aggressive, with YAP1 overexpression associated with poor outcomes in pediatric patients. In this study, we investigated the mechanisms by which YAP1 drives ACC progression and explored it as a potential target therapy.
YAP1 expression and methylation in ACC were analyzed from pediatric and adult cohorts. The role of YAP1 on ACC progression was examined in vitro using an adrenocortical cell line. Also, was evaluated the YAP1's influence on beta-catenin. The effect of YAP1 pharmacological inhibition was assessed on tumor growth in a murine xenograft model of ACC.
High YAP1 expression was associated with lower survival in all cohorts. YAP1 methylation signature associated with patients' prognosis. The inhibition of YAP1 reduced ACC cell viability through cell cycle arrest in the G0-G1 phase, inhibited the epithelial-mesenchymal transition, and cell invasion. YAP1 modulated beta-catenin protein levels and transcription activity, whereas beta-catenin partially mediated the effect of YAP1 on adrenocortical tumorigenesis. In vivo, verteporfin impaired tumor growth and Ki67 immunoreactivity in xenografts.
YAP1 is a potential novel prognostic marker in ACC patients. Its deregulation contributes to adrenocortical tumorigenesis partially through crosstalk between Hippo/YAP1 and Wnt/beta-catenin pathways. YAP1 inhibition is a new antitumor target.
肾上腺皮质癌（ACC）罕见且侵袭性强，YAP1过表达与儿科患者的不良预后相关。在本研究中，我们调查了YAP1驱动ACC进展的机制，并将其作为一种潜在的靶向治疗方法进行探索。
分析了儿科和成人队列中ACC的YAP1表达和甲基化情况。使用肾上腺皮质细胞系在体外研究了YAP1对ACC进展的作用。此外，评估了YAP1对β-连环蛋白的影响。在ACC的小鼠异种移植模型中评估了YAP1药物抑制对肿瘤生长的影响。
在所有队列中，高YAP1表达与较低的生存率相关。YAP1甲基化特征与患者预后相关。YAP1的抑制通过使细胞周期停滞在G0-G1期降低了ACC细胞活力，抑制了上皮-间质转化和细胞侵袭。YAP1调节β-连环蛋白的蛋白水平和转录活性，而β-连环蛋白部分介导了YAP1对肾上腺皮质肿瘤发生的作用。在体内，维替泊芬损害了异种移植瘤的生长和Ki67免疫反应性。
YAP1是ACC患者潜在的新型预后标志物。其失调部分通过Hippo/YAP1和Wnt/β-连环蛋白通路之间的串扰促进肾上腺皮质肿瘤发生。YAP1抑制是一种新的抗肿瘤靶点。
