Distinct and Overlapping Roles of Hippo Effectors YAP and TAZ During Human and Mouse Hepatocarcinogenesis

Abstract

Background & Aims 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. Methods 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. Results 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. Conclusions 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.

Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma

“…In this context, YAP-dependent proliferation of liver cells is leading to the accumulation of mutations and the induction of chromosomal instability (CIN) [ 3 ]. However, the oncogenic role of TAZ in hepatocarcinogenesis is less defined, although previous results illustrated both tumor-initiating and tumor-supporting properties [ 6 , 7 ]. In addition, recent data demonstrated that TAZ cooperates with YAP in HCC progression [ 7 ].…”

SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma

“…Furthermore, we showed that high SOX9 expression correlated with molecular pathways critical for HCC carcinogenesis (YAP-TAZ) 16,36. Very recent work has shown that SOX9 is required for Yap-induced hepatocyte plasticity during hepatocarcinogenesis in mice and, using transcriptomic profiling of 236 liver tumor samples from Japanese patients, YAP activity and SOX9 expression were found to be strongly correlated with liver tumor plasticity in human patients.…”

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

“…TAZ expression significantly correlates with aggressive HCC features, including tumor size, TNM stage, lymph node or distant metastasis, histological differentiation, recurrence, and poor prognosis [ 28 ]. Furthermore, forced overexpression of TAZ promotes cell proliferation, migration, and invasion of HCC cell lines in vitro , whereas opposite effects accompany TAZ knockdown [ 28 , 29 ]. In iCCA, recent studies indicate that TAZ expression is more pronounced in tumor tissues than in the peritumoral counterpart [ 30 , 31 ].…”