Preziosi, Morgan; Poddar, Minakshi; Singh, Sucha; Monga, Satdarshan P. “Hepatocyte Wnts are dispensable during diethylnitrosamine and carbon tetrachloride-induced injury and hepatocellular cancer.” Gene Expr. 2018 Mar 8. doi: 10.3727/105221618X15205148413587. [Epub ahead of print]
ABSTRACT: Activation of the Wnt/β-catenin signaling is reported in large subsets of hepatocellular carcinoma (HCC). Upregulationof Wnt genes is one contributing mechanism. In the current study, we sought to address the role of hepatocyte-derived Wnts in a model of hepatic injury, fibrosis and carcinogenesis. We subjected hepatocyte-specific Wntless knockout mice (HP-KO), unable to secrete Wnts from hepatocytes, and littermate controls (HP-CON), to diethylnitrosamine and carbon tetrachloride (DEN/CCl4) and harvested at 3, 5, and 6 months for histological and molecular analysis. Analysis at 5 months displayed increased hepatic expression of several Wnts and upregulation of some but not all β-catenin targets, without mutations in Ctnnb1. At 5 months, HP-CON and HP-KO had comparable tumor burden and injury, however HP-KO uniquely showed small CK19-positive foci within tumors. At 6 months both groups were moribund with comparable tumor burden and CK19-positivity. While HCC histology was indistinguishable between the groups, HP-KO exhibited increased active-β-catenin, and decreased c-Myc, Brd4, E-Cadherin, and others. Hepatic injury, inflammation and fibrosis were also indistinguishable at 3 months between both groups. Thus, lack of Wnt secretion from hepatocytes did not affect overall injury, fibrosis or HCC burden although there were protein expression differences in the tumors occurring in the two groups.
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