Abstract
ObjectiveChronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50–60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2−/− mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC.MethodsHepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2−/− mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging.ResultsUnlike controls, Mdr2−/− mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality.ConclusionsHh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.
Highlights
Hepatocellular carcinoma (HCC) is an insidious cancer that accounts for up to 1 million deaths a year and is the third leading cause of cancer deaths worldwide [1]
Mice were treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging
Compared to liver protein lysates from wild type controls, lysates from Mdr22/2 mice demonstrated an increase in Sonic hedgehog (Shh) and Indian hedgehog (Ihh) by Western blot analysis
Summary
Hepatocellular carcinoma (HCC) is an insidious cancer that accounts for up to 1 million deaths a year and is the third leading cause of cancer deaths worldwide [1]. A consequence of progressive liver injury and fibrosis, is the single largest risk factor for HCC [2]. Loss-of-function mutations in the hepatocyte canalicular phospholipid flippase MDR3 (ABCB4) have been associated with a wide range of human biliary diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3), cholestasis of pregnancy, drug induced cholestasis and an adult biliary cirrhosis with features similar to primary sclerosing cholangitis (PSC) [4,5,6,7]. The absence of phospholipids in bile results in progressive sclerosing cholangitis with accompanying portal inflammation, ductular proliferation and portal fibrosis. Unlike xenograft models that are widely utilized to examine mechanisms ofand treatments for- HCC, Mdr22/2 mice provide a model that parallels the natural evolution of HCC on a background of chronic inflammation, liver injury and fibrosis [15]
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