Distinct and Overlapping Roles of Hippo Effectors YAP and TAZ During Human and Mouse Hepatocarcinogenesis
| Autor: | Shanshan Zhang, Antonio Cigliano, Xianqiong Liu, Xinhua Song, Jie Zhang, Pan Wang, Yong Zeng, Xin Chen, Matthias Evert, Haichuan Wang, Ke Liu, Diego F. Calvisi, Jingxiao Wang, Hong Wu, Jiaoyuan Jia, Silvia Ribback, Li Che |
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| Rok vydání: | 2021 |
| Předmět: |
Male
TAZ 0301 basic medicine Neuroblastoma RAS viral oncogene homolog YAP yes-associated protein Cell Cycle Proteins law.invention BrdU bromodeoxyuridine Mice LATS1/2 large tumor-suppressor kinase 1/2 0302 clinical medicine law NEDD4 developmentally down-regulated protein 4 siYT small interfering RNA targeting yes-associated protein/transcriptional co-activator with PDZ-binding motif Original Research Mice Knockout siTAZ small interfering targeting transcriptional co-activator with PDZ-binding motif TCGA the cancer genome atlas ICC intrahepatic cholangiocarcinoma pCMV cytomegalovirus promoter V12 mutation at position 12 replacing amino acid glycine with valine Liver Neoplasms Cell Cycle Gastroenterology Hepatitis B PTX3 pentraxin 3 mRNA messenger RNA NRas Neuroblastoma Ras viral oncogene homolog Knockout mouse qPCR quantitative polymerase chain reaction Female 030211 gastroenterology & hepatology YAP IHC immunohistochemistry TEAD TEA domain Hepatitis B virus Carcinoma Hepatocellular TAZ transcriptional co-activator with PDZ-binding motif Biology 03 medical and health sciences Neuroblastoma KEGG Kyoto encyclopedia of genes and genomes medicine Animals Humans Gene silencing lcsh:RC799-869 Gene Protein kinase B Aged KO knockout Hepatology myr-Akt-HA myristoylated-protein kinase B-hemagglutinin tag p-Erk1/2 phosphorylated extracellular regulated kinase 1/2 YAP-Signaling Proteins Hepatocellular Carcinoma HCCS siSC scrambled small interfering RNA medicine.disease 030104 developmental biology siYAP small interfering RNA targeting yes-associated protein siRNA small interfering RNA Ct cycle threshold Akt protein kinase B Cancer research Suppressor lcsh:Diseases of the digestive system. Gastroenterology HCC hepatocellular carcinoma Acyltransferases MAPK mitogen-activated protein kinase Transcription Factors |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and molecular gastroenterology and hepatology, vol 11, iss 4 Cellular and Molecular Gastroenterology and Hepatology, Vol 11, Iss 4, Pp 1095-1117 (2021) |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2020.11.008 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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