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Hepatocyte Wnts Are Dispensable During Diethylnitrosamine and Carbon Tetrachloride-Induced Injury and Hepatocellular Cancer

Morgan Preziosi, Minakshi Poddar, Sucha Singh, Satdarshan P Monga
Gene Expression 2018 August 22, 18 (3): 209-219
Activation of the Wnt/β-catenin signaling is reported in large subsets of hepatocellular carcinoma (HCC). Upregulation of 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+ 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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