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. Graphical abstract
【저자키워드】 cell cycle, Hepatocellular carcinoma, CT, Cycle threshold, MAPK, Mitogen-activated protein kinase, IHC, immunohistochemistry, HCC, hepatocellular carcinoma, YAP, TAZ, Akt, protein kinase B, BrdU, bromodeoxyuridine, ICC, intrahepatic cholangiocarcinoma, KEGG, Kyoto encyclopedia of genes and genomes, KO, knockout, LATS1/2, large tumor-suppressor kinase 1/2, mRNA, messenger RNA, myr-Akt-HA, myristoylated-protein kinase B-hemagglutinin tag, NEDD4, developmentally down-regulated protein 4, NRas, Neuroblastoma Ras viral oncogene homolog, pCMV, cytomegalovirus promoter, p-Erk1/2, phosphorylated extracellular regulated kinase 1/2, PTX3, pentraxin 3, qPCR, quantitative polymerase chain reaction, siRNA, small interfering RNA, siSC, scrambled small interfering RNA, siTAZ, small interfering targeting transcriptional co-activator with PDZ-binding motif, TAZ, transcriptional co-activator with PDZ-binding motif, siYAP, small interfering RNA targeting yes-associated protein, siYT, small interfering RNA targeting yes-associated protein/transcriptional co-activator with PDZ-binding motif, TCGA, the cancer genome atlas, TEAD, TEA domain, V12, mutation at position 12 replacing amino acid glycine with valine, YAP, yes-associated protein,