title: YAP activation is an early event and a potential therapeutic target in liver cancer development.
abstract: OBJECTIVE
  Although the growth suppressing Hippo pathway has been implicated in hepatocellular carcinoma (HCC) pathogenesis, it is unknown at which stage of hepatocarcinogenesis its dysregulation occurs. We investigated in rat and human preneoplastic lesions whether overexpression of the transcriptional co-activator Yes-associated protein (YAP) is an early event.
  
  
  METHODS
  The experimental model used is the resistant-hepatocyte (R-H) rat model. Gene expression was determined by qRT-PCR or immunohistochemistry. Forward genetic experiments were performed in human HCC cells and in murine oval cells.
  
  
  RESULTS
  All foci of preneoplastic hepatocytes, generated in rats 4weeks after diethylnitrosamine (DENA) treatment, displayed YAP accumulation. This was associated with down-regulation of the β-TRCP ligase, known to mediate YAP degradation, and of microRNA-375, targeting YAP. YAP accumulation was paralleled by the up-regulation of its target genes. Increased YAP expression was also observed in human early dysplastic nodules and adenomas. Animal treatment with verteporfin (VP), which disrupts the formation of the YAP-TEAD complex, significantly reduced preneoplastic foci and oval cell proliferation. In vitro experiments confirmed that VP-mediated YAP inhibition impaired cell growth in HCC and oval cells; notably, oval cell transduction with wild type or active YAP conferred tumorigenic properties in vitro and in vivo.
  
  
  CONCLUSIONS
  These results suggest that (i) YAP overexpression is an early event in rat and human liver tumourigenesis; (ii) it is critical for the clonal expansion of carcinogen-initiated hepatocytes and oval cells, and (iii) VP-induced disruption of the YAP-TEAD interaction may provide an important approach for the treatment of YAP-overexpressing cancers.
authors.affiliation: Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Perra
authors.affiliation: Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy.
authors.forename: Marta Anna
authors.initials: MA
authors.lastname: Kowalik
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute - FPO, IRCCS, 10060 Candiolo (Torino), Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ghiso
authors.affiliation: Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy.
authors.forename: Giovanna Maria
authors.initials: GM
authors.lastname: Ledda-Columbano
authors.affiliation: University of Milano and Humanitas Clinical and Research Center, Rozzano, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Di Tommaso
authors.affiliation: Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Maddalena
authors.initials: MM
authors.lastname: Angioni
authors.affiliation: University of Milano and Humanitas Clinical and Research Center, Rozzano, Milano, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Raschioni
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute - FPO, IRCCS, 10060 Candiolo (Torino), Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Testore
authors.affiliation: University of Milano and Humanitas Clinical and Research Center, Rozzano, Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute - FPO, IRCCS, 10060 Candiolo (Torino), Italy. Electronic address: silvia.giordano@unito.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
authors.affiliation: Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy. Electronic address: columbano@unica.it.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D018248:Adenoma, Liver Cell / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D000090683:Hippo Signaling Pathway; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism*; D011166:Porphyrins / Q000494:pharmacology; D011230:Precancerous Conditions / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D014157:Transcription Factors; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D011166:Porphyrins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; C509425:Yap1 protein, rat; D000077362:Verteporfin; D017346:Protein Serine-Threonine Kinases
keywords: HCC; Hippo pathway; Preneoplastic stages; TCPOBOP; Verteporfin