YAP activation is an early event and a potential therapeutic target in liver cancer development

Andrea Perra, Marta Anna Kowalik, Elena Ghiso, Giovanna Maria Ledda-Columbano, Luca Di Tommaso, Maria Maddalena Angioni, Carlotta Raschioni, Elena Testore, Massimo Roncalli, Silvia Giordano, Amedeo Columbano

Research output: Contribution to journalArticlepeer-review

Abstract

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 4 weeks 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.

Original languageEnglish
Pages (from-to)1088-1096
Number of pages9
JournalJournal of Hepatology
Volume61
Issue number5
DOIs
Publication statusPublished - 2014

Keywords

  • HCC
  • Hippo pathway
  • Preneoplastic stages
  • TCPOBOP
  • Verteporfin

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

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