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 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.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Perra A,Kowalik MA,Ghiso E,Ledda-Columbano GM,Di Tommaso L,Angioni MM,Raschioni C,Testore E,Roncalli M,Giordano S,Columbano Adoi
10.1016/j.jhep.2014.06.033subject
Has Abstractpub_date
2014-11-01 00:00:00pages
1088-96issue
5eissn
0168-8278issn
1600-0641pii
S0168-8278(14)00463-2journal_volume
61pub_type
杂志文章abstract:BACKGROUND & AIMS:Roles of alcohol consumption in non-alcoholic fatty liver disease are still controversial, although several cross-sectional studies have suggested the beneficial effect of light to moderate drinking on fatty liver. We analyzed the longitudinal relationship between drinking pattern and fatty liver. ME...
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abstract::We have studied the roles of immunoprophylaxis, patient selection policy and coexistent hepatitis D virus infection in the outcome of 56 HBsAg-positive elective liver transplant recipients. Twenty-nine unselected patients not treated with immunoprophylaxis formed group 1 and were compared to a recent consecutive serie...
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abstract::Ciprofloxacin, a fluorinated quinolone, is a powerful antibiotic widely used for its broad spectrum of activity in ambulatory and long-term care setting. Until now, ciprofloxacin administration has been associated with a few cases of acute, sometimes cholestatic jaundice or fulminant hepatic failure believed mainly re...
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abstract:BACKGROUND/AIMS:Currently the diagnosis and severity of hepatic steatosis can be established accurately only by liver biopsy. Previous small studies found that steatosis measured by magnetic resonance spectroscopy (MRS) and imaging (MRI) correlated with histological assessment of liver triglyceride content. However, th...
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更新日期:1995-04-01 00:00:00
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