title: Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease.
abstract: Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14-3-3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells.
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Simile
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
authors.forename: Gavinella
authors.initials: G
authors.lastname: Latte
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Demartis
authors.affiliation: Department of Surgery ''Pietro Valdoni'', University of Rome 'Sapienza'', Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Brozzetti
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Surgery, University of Sassari, Sassari, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Porcu
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Surgery, University of Sassari, Sassari, Italy.
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Feo
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Seddaiu
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Daino
authors.affiliation: Division of Hepatology, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain.|CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.|IDISNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.affiliation: Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Tomasi
authors.affiliation: Division of Hepatology, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain.|CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.|IDISNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Matias A
authors.initials: MA
authors.lastname: Avila
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Feo
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Pascale
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000166:cytology; D009687:Nuclear Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C509425:Yap1 protein, rat; D053148:Caspase 3
keywords: YAP targets; gene expression profile; hepatocarcinogenesis; progression; stem cells