The Hippo kinase cascade, a growth-suppressive pathway that ultimately antagonizes the transcriptional coactivator Yes-associated protein (YAP), has been shown in transgenic animals to orchestrate organ size regulation. The purpose of this study was to determine whether in non-genetically modified mice (1) the Hippo pathway is involved in the regulation of adaptive liver enlargement caused by the mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), an agonist of constitutive androstane receptor and (2) a dysregulation of this pathway occurs during the development of chemically induced hepatocellular carcinoma (HCC). We show that liver enlargement caused by TCPOBOP was associated with an increase of YAP protein levels that paralleled the increase in 2-bromodeoxyuridine incorporation. Interestingly, when a second dose of TCPOBOP was given to mice with enlarged livers, no further increases in liver mass or YAP protein levels were observed, suggesting that the Hippo pathway prevents further growth of the hyperplastic liver. Viral-mediated exogenous expression of active YAP in mouse livers was able to partially overcome the block of hepatocyte proliferation. We also show that HCCs developed in mice given diethylnitrosamine and then subjected to repeated treatments with TCPOBOP had increased levels of YAP that were associated with down-regulation of microRNA 375, which is known to control YAP expression, and with enhanced levels of alpha-fetoprotein and connective tissue growth factor, two target genes of YAP. Conclusion:: These results suggest that the Hippo pathway regulates adaptive liver enlargement and is probably inactivated in initiated cells that escape the suppressive constrain exerted on the surrounding normal tissue, thus allowing clonal expansion to HCC.
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