| First Author | Yang L | Year | 2013 |
| Journal | Gastroenterology | Volume | 144 |
| Issue | 5 | Pages | 1042-1054.e4 |
| PubMed ID | 23391818 | Mgi Jnum | J:310605 |
| Mgi Id | MGI:6763726 | Doi | 10.1053/j.gastro.2013.01.056 |
| Citation | Yang L, et al. (2013) Transforming growth factor-beta signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1. Gastroenterology 144(5):1042-1054.e4 |
| abstractText | BACKGROUND & AIMS: Transforming growth factor (TGF)-beta-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-beta activates TAK1 and Smad signaling, which regulate cell death, proliferation, and carcinogenesis. However, it is not clear whether TGF-beta signaling in hepatocytes, via TGF-beta receptor-2 (Tgfbr2), promotes HCC and liver fibrosis. METHODS: We generated mice with hepatocyte-specific deletion of Tak1 (Tak1DeltaHep), as well as Tak1/Tgfbr2DHep and Tak1/Smad4DeltaHep mice. Tak1flox/flox, Tgfbr2DeltaHep, and Smad4DeltaHep 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-beta-mediated signaling. RESULTS: Levels of TGF-beta, TGF-betaR2, and phospho-Smad2/3 were increased in HCCs from Tak1DeltaHep mice, which developed liver fibrosis and inflammation by 1 month and HCC by 9 months. However, Tak1/Tgfbr2DeltaHep mice did not have this phenotype, and their hepatocytes did not undergo spontaneous cell death or compensatory proliferation. Hepatocytes from Tak1DeltaHep mice incubated with TGF-beta did not activate p38, c-Jun N-terminal kinase, or nuclear factor-kappaB; conversely, TGF-beta-mediated cell death and phosphorylation of Smad2/3 were increased, compared with control hepatocytes. Blocking the Smad pathway inhibited TGF-beta-mediated death of Tak1-/- hepatocytes. Accordingly, disruption of Smad4 reduced the spontaneous liver injury, inflammation, fibrosis, and HCC that develops in Tak1DeltaHep mice. Levels of the anti-apoptotic protein Bcl-xL, beta-catenin, connective tissue growth factor, and vascular endothelial growth factor were increased in HCC from Tak1DeltaHep mice, but not in HCCs from Tak1/Tgfbr2DeltaHep mice. Injection of N-nitrosodiethylamine induced HCC formation in wild-type mice, but less in Tgfbr2DeltaHep mice. CONCLUSIONS: TGF-beta promotes development of HCC in Tak1DeltaHep 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. |
