Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Medical Faculty Mannheim, Medical Research Center, University of Heidelberg, Mannheim, Germany.
Cancer Lett. 2020 Mar 31;473:164-175. doi: 10.1016/j.canlet.2019.12.044. Epub 2020 Jan 3.
The Hippo pathway effectors yes-associated protein (YAP) and WW domain containing transcription regulator 1 (TAZ/WWTR1) support tumor initiation and progression in various cancer entities including hepatocellular carcinoma (HCC). However, to which extent YAP and TAZ contribute to liver tumorigenesis via common and exclusive molecular mechanisms is poorly understood. RNAinterference (RNAi) experiments illustrate that YAP and TAZ individually support HCC cell viability and migration, while for invasion additive effects were observed. Comprehensive expression profiling revealed partly overlapping YAP/TAZ target genes as well as exclusively regulated genes. Integrin-αV (ITGAV) is a novel TAZ-specific target gene, whose overexpression in human HCC patients correlates with poor clinical outcome, TAZ expression in HCCs, and the abundance of YAP/TAZ target genes. Functionally, ITGAV contributes to actin stress fiber assembly, tumor cell migration and invasion. Perturbation of ITGAV diminishes actin fiber formation and nuclear YAP/TAZ protein levels. We describe a novel Hippo downstream mechanism in HCC cells, which is regulated by TAZ and ITGAV and that feedbacks on YAP/TAZ activity. This mechanism may represent a therapeutic target structure since it contributes to signal amplification of oncogenic YAP/TAZ in hepatocarcinogenesis.
Hippo 通路效应物 yes 相关蛋白 (YAP) 和包含 WW 结构域的转录调节剂 1 (TAZ/WWTR1) 支持多种癌症实体中的肿瘤起始和进展，包括肝细胞癌 (HCC)。然而，YAP 和 TAZ 通过共同和独特的分子机制在多大程度上促进肝肿瘤发生尚不清楚。RNA 干扰 (RNAi) 实验表明，YAP 和 TAZ 各自支持 HCC 细胞的活力和迁移，而侵袭则观察到相加效应。综合表达谱分析显示部分重叠的 YAP/TAZ 靶基因以及特异性调控的基因。整合素-αV (ITGAV) 是 TAZ 特异性的新靶基因，其在人类 HCC 患者中的过表达与不良临床结局、HCC 中的 TAZ 表达以及 YAP/TAZ 靶基因的丰度相关。功能上，ITGAV 有助于肌动蛋白应力纤维组装、肿瘤细胞迁移和侵袭。干扰 ITGAV 会减少肌动蛋白纤维的形成和核 YAP/TAZ 蛋白水平。我们描述了 HCC 细胞中一种新的 Hippo 下游机制，该机制受 TAZ 和 ITGAV 调节，并反馈 YAP/TAZ 活性。该机制可能代表一种治疗性靶结构，因为它有助于在肝癌发生中信号放大致癌性 YAP/TAZ。
