García Patricia, Rosa Lorena, Vargas Sergio, Weber Helga, Espinoza Jaime A, Suárez Felipe, Romero-Calvo Isabel, Elgueta Nicole, Rivera Vanessa, Nervi Bruno, Obreque Javiera, Leal Pamela, Viñuela Eduardo, Aguayo Gloria, Muñiz Sabrina, Sagredo Alfredo, Roa Juan C, Bizama Carolina
Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
Applied Molecular and Cellular Biology PhD Program, Universidad de La Frontera, Temuco 4811230, Chile.
Cancers (Basel). 2020 Mar 25;12(4):778. doi: 10.3390/cancers12040778.
Gallbladder cancer is an aggressive disease with late diagnosis and no efficacious treatment. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway has emerged as a target for the development of new therapeutic interventions in cancers. However, the role of the Hippo-targeted therapy has not been addressed in advanced gallbladder cancer (GBC). This study aimed to evaluate the expression of the major Hippo pathway components mammalian Ste20-like protein kinase 1 (MST1), YAP1 and transcriptional coactivator with PDZ-binding motif (TAZ) and examined the effects of Verteporfin (VP), a small molecular inhibitor of YAP1-TEA domain transcription factor (TEAD) protein interaction, in metastatic GBC cell lines and patient-derived organoids (PDOs). Immunohistochemical analysis revealed that advanced GBC patients had high nuclear expression of YAP1. High nuclear expression of YAP1 was associated with poor survival in GBC patients with subserosal invasion (pT2). Additionally, advanced GBC cases showed reduced expression of MST1 compared to chronic cholecystitis. Both VP treatment and YAP1 siRNA inhibited the migration ability in GBC cell lines. Interestingly, gemcitabine resistant PDOs with high nuclear expression of YAP1 were sensitive to VP treatment. Taken together, our results suggest that key components of the Hippo-YAP1 signaling pathway are dysregulated in advanced gallbladder cancer and reveal that the inhibition YAP1 may be a candidate for targeted therapy.
胆囊癌是一种侵袭性疾病，诊断较晚且缺乏有效的治疗方法。Hippo-Yes相关蛋白1（YAP1）信号通路已成为癌症新治疗干预措施开发的靶点。然而，Hippo靶向治疗在晚期胆囊癌（GBC）中的作用尚未得到研究。本研究旨在评估Hippo通路主要成分哺乳动物Ste20样蛋白激酶1（MST1）、YAP1和含PDZ结合基序的转录共激活因子（TAZ）的表达，并研究YAP1-TEA结构域转录因子（TEAD）蛋白相互作用的小分子抑制剂维替泊芬（VP）对转移性GBC细胞系和患者来源类器官（PDO）的影响。免疫组织化学分析显示，晚期GBC患者YAP1核表达较高。YAP1高核表达与浆膜下浸润（pT2）的GBC患者生存率低相关。此外，与慢性胆囊炎相比，晚期GBC病例MST1表达降低。VP处理和YAP1 siRNA均抑制GBC细胞系的迁移能力。有趣的是，YAP1核表达高的吉西他滨耐药PDO对VP处理敏感。综上所述，我们的结果表明，Hippo-YAP1信号通路的关键成分在晚期胆囊癌中失调，并表明抑制YAP1可能是靶向治疗的一个候选方案。
