YAP activation is an early event and a potential therapeutic target in liver cancer development
PERRA, ANDREA;Kowalik MA;LEDDA, GIOVANNA MARIA;ANGIONI, MARIA MADDALENA;COLUMBANO, AMEDEO
2014-01-01
Abstract
Background and Aims: Although the growth suppressor Hippo pathway has been implicated in hepatocellular carcinoma (HCC) pathogenesis, it is unknown at which stage of hepatocarcinogenesis its dysregulation occurs. We investigated in early 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 up-regulation of its target genes. Increased YAP expression was also observed in early dysplastic nodules and adenomas in humans. 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 tumorigenesis; ii) it is critical for the clonal expansion of carcinogen-initiated hepatocytes and oval cells, and, iii) VP-induced disruption of YAP-TEAD interaction may provide an important approach for the treatment of YAP-overexpressing cancers.File | Size | Format | |
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YAP J Hepatol.pdf Solo gestori archivio
Size 2.79 MB
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2.79 MB | Adobe PDF | & nbsp; View / Open Request a copy |
YAP accepted manuscript.pdf open access
Description: Principal articol, post-print version
Type: versione post-print
Size 636.97 kB
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636.97 kB | Adobe PDF | View/Open |
Decision Letter.pdf open access
Description: Editor's decision letter
Type: altro documento allegato
Size 67.97 kB
Format Adobe PDF
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67.97 kB | Adobe PDF | View/Open |
Editorial YAP.pdf Solo gestori archivio
Description: Editorial
Type: altro documento allegato
Size 305.45 kB
Format Adobe PDF
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305.45 kB | Adobe PDF | & nbsp; View / Open Request a copy |
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