Distinct and Overlapping Roles of Hippo Effectors YAP and TAZ During Human and Mouse Hepatocarcinogenesis.
Distinct and Overlapping Roles of Hippo Effectors YAP and TAZ During Human and Mouse Hepatocarcinogenesis.
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河马效应因子YAP和TAZ在人和小鼠肝癌发生中的不同和重叠作用
DOI：
10.1016/j.jcmgh.2020.11.008
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发表时间：
2021
影响因子：
7.2
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Wang H;Wang J;Zhang S;Jia J;Liu X;Zhang J;Wang P;Song X;Che L;Liu K;Ribback S;Cigliano A;Evert M;Wu H;Calvisi DF;Zeng Y;Chen X
yes相关蛋白（YAP）及其与突触后密度蛋白、果蝇盘状大肿瘤抑制因子和封闭带1结合基序（TAZ）的副转录共激活因子是Hippo肿瘤抑制因子级联下游的2个共激活因子。两者都与肝细胞癌（HCC）的发展有关。然而，在肝癌发生过程中，YAP和TAZ是否具有不同或重叠的功能尚不清楚。分析了YAP和TAZ在人肝癌中的表达模式。使用条件Yap、Taz和Yap分析Yap和/或Taz在蛋白激酶B (Akt)/神经母细胞瘤RAS病毒癌基因同源物（NRas）驱动的肝脏肿瘤发生中的需求；Taz基因敲除小鼠。通过RNA测序鉴定YAP和/或TAZ调控的转录程序。我们发现，在人类HCC样本中，几乎无处不在的YAP或TAZ激活发生，这是它们在这种肿瘤类型中的作用。有趣的是，70%的HCC样本仅显示核YAP或TAZ免疫反应性。在Akt/NRas肝肿瘤模型中，细胞核Yap和Taz很容易被检测到，单独删除Yap或Taz只会轻度延迟肝肿瘤的发展，而它们的联合消融则会强烈抑制肿瘤细胞的增殖，并显著抑制Akt/NRas驱动的肝癌发生。在HCC细胞系中，YAP或TAZ的沉默导致重叠和不同基因组的表达减少，其中最突出的基因特征与细胞周期进展和DNA复制相关。YAP和TAZ在肝癌发生中具有重叠和不同的作用。hcc可能表现出独特的YAP或TAZ激活，因此依赖于YAP或TAZ的生长。
Yes-associated protein (YAP) and its paralog transcriptional co-activator with post synaptic density protein, drosophila disc large tumor suppressor and zonula occludens-1-binding motif (TAZ) are 2 co-activators downstream of Hippo tumor-suppressor cascade. Both have been implicated in the development of hepatocellular carcinoma (HCC). However, whether YAP and TAZ have distinct or overlapping functions during hepatocarcinogenesis remains unknown. Expression patterns of YAP and TAZ were analyzed in human HCC samples. The requirement of Yap and/or Taz in protein kinase B (Akt)/ neuroblastoma RAS viral oncogene homolog (NRas) -driven liver tumorigenesis was analyzed using conditional Yap, Taz, and Yap;Taz knockout mice. Transcriptional programs regulated by YAP and/or TAZ were identified via RNA sequencing. We found that in human HCC samples, an almost ubiquitous activation of YAP or TAZ occurs, underlying their role in this tumor type. Intriguingly, 70% of HCC samples showed only nuclear YAP or TAZ immunoreactivity. In the Akt/NRas liver tumor model, where nuclear Yap and Taz can be detected readily, deletion of Yap or Taz alone only mildly delayed liver tumor development, whereas their concomitant ablation strongly inhibited tumor cell proliferation and significantly suppressed Akt/NRas-driven hepatocarcinogenesis. In HCC cell lines, silencing of either YAP or TAZ led to decreased expression of both overlapping and distinct sets of genes, with the most prominent gene signatures related to cell-cycle progression and DNA replication. YAP and TAZ have overlapping and distinct roles in hepatocarcinogenesis. HCCs may display unique activation of YAP or TAZ, thus relying on either YAP or TAZ for their growth.
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