Annals of surgical oncology · 2026
An Integrated Cell-Death Program Defines Aggressive Prostate Cancer by Coupling Ezrin to the Hippo-YAP/TAZ Axis.
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Luo Xing, Huang Zeyu, Deng Min, Liu Jingui, Liao Chaoyu, Yang Youhao, Meng Zhaoyu, Yuan Jianxu, Xu Jiahao, Liu Yuxuan, Wang Qiulin, Wang Zhihao, Li Hao, Shi Ronghui, Zeng Han, Su Shuai, Liu Liang, Zheng Ji
Аннотация
BACKGROUND: Prostate cancer (PCa) exhibits highly heterogeneous clinical outcomes, underscoring the need for biomarkers that more closely reflect tumor biology. While programmed cell death (PCD) is fundamental to tumor suppression, the prognostic impact of individual PCD pathways remains poorly characterized in PCa.
METHODS: We constructed 14 PCD prognostic models in a training cohort (GSE116918, n = 248), integrated the top three (apoptosis, entosis, necroptosis) into an AEN score, and validated in two independent cohorts in PCa. Tumor microenvironment (TME), drug sensitivity, single‑cell trajectories, Mendelian randomization, and functional assays were performed.
RESULTS: The AEN score outperformed single models (AUC = 0.857) and independently predicted biochemical recurrence (HR = 8.02). High‑AEN tumors exhibited a non‑inflamed TME, predicted immunotherapy resistance, yet increased chemosensitivity. EZR was nominated as a causal driver; knockdown of EZR suppressed proliferation, migration, and tumor growth via YAP/TAZ dysregulation.
CONCLUSIONS: The AEN score is a robust prognostic tool linking PCD activity to PCa aggressiveness and immune evasion. EZR emerges as a functional effector and potential therapeutic target acting through Hippo signaling in PCa.
METHODS: We constructed 14 PCD prognostic models in a training cohort (GSE116918, n = 248), integrated the top three (apoptosis, entosis, necroptosis) into an AEN score, and validated in two independent cohorts in PCa. Tumor microenvironment (TME), drug sensitivity, single‑cell trajectories, Mendelian randomization, and functional assays were performed.
RESULTS: The AEN score outperformed single models (AUC = 0.857) and independently predicted biochemical recurrence (HR = 8.02). High‑AEN tumors exhibited a non‑inflamed TME, predicted immunotherapy resistance, yet increased chemosensitivity. EZR was nominated as a causal driver; knockdown of EZR suppressed proliferation, migration, and tumor growth via YAP/TAZ dysregulation.
CONCLUSIONS: The AEN score is a robust prognostic tool linking PCD activity to PCa aggressiveness and immune evasion. EZR emerges as a functional effector and potential therapeutic target acting through Hippo signaling in PCa.
Предметные рубрики MeSH
HumansMaleProstatic NeoplasmsPrognosisProtein Serine-Threonine KinasesTranscription FactorsEzrinYAP-Signaling ProteinsHippo Signaling PathwayCytoskeletal ProteinsBiomarkers, TumorTrans-ActivatorsSignal TransductionTumor MicroenvironmentCell ProliferationApoptosisAdaptor Proteins, Signal TransducingTranscriptional Coactivator with PDZ-Binding Motif ProteinsAnimalsCell Movement