title: Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1.
abstract: OBJECTIVE
  Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) is activated in different cytokine signaling pathways. Deletion of Tak1 from hepatocytes results in spontaneous development of hepatocellular carcinoma (HCC), liver inflammation, and fibrosis. TGF-β activates TAK1 and Smad signaling, which regulate cell death, proliferation, and carcinogenesis. However, it is not clear whether TGF-β signaling in hepatocytes, via TGF-β receptor-2 (Tgfbr2), promotes HCC and liver fibrosis.
  
  
  METHODS
  We generated mice with hepatocyte-specific deletion of Tak1 (Tak1ΔHep), as well as Tak1/Tgfbr2DHep and Tak1/Smad4ΔHep mice. Tak1flox/flox, Tgfbr2ΔHep, and Smad4ΔHep mice were used as controls, respectively. We assessed development of liver injury, inflammation, fibrosis, and HCC. Primary hepatocytes isolated from these mice were used to assess TGF-β-mediated signaling.
  
  
  RESULTS
  Levels of TGF-β, TGF-βR2, and phospho-Smad2/3 were increased in HCCs from Tak1ΔHep mice, which developed liver fibrosis and inflammation by 1 month and HCC by 9 months. However, Tak1/Tgfbr2ΔHep mice did not have this phenotype, and their hepatocytes did not undergo spontaneous cell death or compensatory proliferation. Hepatocytes from Tak1ΔHep mice incubated with TGF-β did not activate p38, c-Jun N-terminal kinase, or nuclear factor-κB; conversely, TGF-β-mediated cell death and phosphorylation of Smad2/3 were increased, compared with control hepatocytes. Blocking the Smad pathway inhibited TGF-β-mediated death of Tak1-/- hepatocytes. Accordingly, disruption of Smad4 reduced the spontaneous liver injury, inflammation, fibrosis, and HCC that develops in Tak1ΔHep mice. Levels of the anti-apoptotic protein Bcl-xL, β-catenin, connective tissue growth factor, and vascular endothelial growth factor were increased in HCC from Tak1ΔHep mice, but not in HCCs from Tak1/Tgfbr2ΔHep mice. Injection of N-nitrosodiethylamine induced HCC formation in wild-type mice, but less in Tgfbr2ΔHep mice.
  
  
  CONCLUSIONS
  TGF-β promotes development of HCC in Tak1ΔHep mice by inducing hepatocyte apoptosis and compensatory proliferation during early phases of tumorigenesis, and inducing expression of anti-apoptotic, pro-oncogenic, and angiogenic factors during tumor progression.
authors: Division of Gastroenterology, Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
authors: Ling
authors: L
authors: Yang
authors: Sayaka
authors: S
authors: Inokuchi
authors: Yoon Seok
authors: YS
authors: Roh
authors: Jingyi
authors: J
authors: Song
authors: Rohit
authors: R
authors: Loomba
authors: Eek Joong
authors: EJ
authors: Park
authors: Ekihiro
authors: E
authors: Seki
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D017353:Gene Deletion; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D004273:DNA, Neoplasm; D020930:MAP Kinase Kinase Kinases; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7
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