PMID- 25010260 OWN - NLM STAT- MEDLINE DCOM- 20150626 LR - 20211203 IS - 1600-0641 (Electronic) IS - 0168-8278 (Linking) VI - 61 IP - 5 DP - 2014 Nov TI - YAP activation is an early event and a potential therapeutic target in liver cancer development. PG - 1088-96 LID - S0168-8278(14)00463-2 [pii] LID - 10.1016/j.jhep.2014.06.033 [doi] AB - BACKGROUND & AIMS: 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 beta-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. CI - Copyright (c) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. FAU - Perra, Andrea AU - Perra A AD - Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy. FAU - Kowalik, Marta Anna AU - Kowalik MA AD - Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy. FAU - Ghiso, Elena AU - Ghiso E AD - Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute - FPO, IRCCS, 10060 Candiolo (Torino), Italy. FAU - Ledda-Columbano, Giovanna Maria AU - Ledda-Columbano GM AD - Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy. FAU - Di Tommaso, Luca AU - Di Tommaso L AD - University of Milano and Humanitas Clinical and Research Center, Rozzano, Milano, Italy. FAU - Angioni, Maria Maddalena AU - Angioni MM AD - Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy. FAU - Raschioni, Carlotta AU - Raschioni C AD - University of Milano and Humanitas Clinical and Research Center, Rozzano, Milano, Italy. FAU - Testore, Elena AU - Testore E AD - Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute - FPO, IRCCS, 10060 Candiolo (Torino), Italy. FAU - Roncalli, Massimo AU - Roncalli M AD - University of Milano and Humanitas Clinical and Research Center, Rozzano, Milano, Italy. FAU - Giordano, Silvia AU - Giordano S AD - Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute - FPO, IRCCS, 10060 Candiolo (Torino), Italy. Electronic address: silvia.giordano@unito.it. FAU - Columbano, Amedeo AU - Columbano A AD - Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy. Electronic address: columbano@unica.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140707 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antineoplastic Agents) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Cell Cycle Proteins) RN - 0 (MIRN375 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Phosphoproteins) RN - 0 (Porphyrins) RN - 0 (Transcription Factors) RN - 0 (YAP-Signaling Proteins) RN - 0 (YAP1 protein, human) RN - 0 (Yap1 protein, mouse) RN - 0 (Yap1 protein, rat) RN - 0X9PA28K43 (Verteporfin) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM CIN - J Hepatol. 2014 Nov;61(5):969-70. PMID: 25149111 CIN - J Hepatol. 2015 Jun;62(6):1444. PMID: 25687424 CIN - J Hepatol. 2015 Jun;62(6):1445. PMID: 25701465 MH - Adaptor Proteins, Signal Transducing/*metabolism MH - Adenoma, Liver Cell/drug therapy/etiology/metabolism MH - Adult MH - Aged MH - Animals MH - Antineoplastic Agents/pharmacology MH - Apoptosis Regulatory Proteins/antagonists & inhibitors/genetics/*metabolism MH - Carcinoma, Hepatocellular/drug therapy/*etiology/*metabolism MH - Cell Cycle Proteins MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Female MH - Gene Expression MH - Hippo Signaling Pathway MH - Humans MH - Liver Neoplasms/drug therapy/*etiology/*metabolism MH - Liver Neoplasms, Experimental/drug therapy/etiology/metabolism MH - Male MH - Mice MH - MicroRNAs/genetics/metabolism MH - Middle Aged MH - Phosphoproteins/*metabolism MH - Porphyrins/pharmacology MH - Precancerous Conditions/drug therapy/etiology/metabolism MH - Protein Serine-Threonine Kinases/metabolism MH - Rats MH - Rats, Inbred F344 MH - Signal Transduction MH - Transcription Factors MH - Verteporfin MH - YAP-Signaling Proteins MH - Young Adult OTO - NOTNLM OT - HCC OT - Hippo pathway OT - Preneoplastic stages OT - TCPOBOP OT - Verteporfin EDAT- 2014/07/11 06:00 MHDA- 2015/06/27 06:00 CRDT- 2014/07/11 06:00 PHST- 2014/04/20 00:00 [received] PHST- 2014/06/12 00:00 [revised] PHST- 2014/06/27 00:00 [accepted] PHST- 2014/07/11 06:00 [entrez] PHST- 2014/07/11 06:00 [pubmed] PHST- 2015/06/27 06:00 [medline] AID - S0168-8278(14)00463-2 [pii] AID - 10.1016/j.jhep.2014.06.033 [doi] PST - ppublish SO - J Hepatol. 2014 Nov;61(5):1088-96. doi: 10.1016/j.jhep.2014.06.033. Epub 2014 Jul 7.