Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1.
Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1.
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DOI：
10.1053/j.gastro.2013.01.056
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发表时间：
2013-05
期刊：
影响因子：
29.4
通讯作者：
Seki E
中科院分区：
文献类型：
--
作者：
Yang L;Inokuchi S;Roh YS;Song J;Loomba R;Park EJ;Seki E
转化生长因子-β激活的激酶1在不同的细胞因子信号通路中被激活。从肝细胞中缺失Tak1会导致肝细胞癌(HCC)的自发发展、肝脏炎症和纤维化。转化生长因子-β激活Tak1和Smad信号，调节细胞死亡、增殖和癌变。然而，目前尚不清楚肝细胞中的转化生长因子-β信号是否通过转化生长因子-β受体-2促进肝细胞癌和肝纤维化。我们产生了肝细胞特异性缺失Tak1(Tak1ΔHep)的小鼠，以及Tak1/Tgfbr2DHep和Tak1/Smad4ΔHep小鼠。分别以Tak1 Flox/Flox、TGFBR2ΔHEP和Smad4ΔHEP小鼠为对照。我们评估了肝损伤、炎症、纤维化和肝细胞癌的发展。从这些小鼠分离的原代肝细胞用于评估转化生长因子-β介导的信号转导。转化生长因子β、转化生长因子βR2和磷酸化Smad2/3在形成肝纤维化和炎症的1个月和发生肝细胞癌9个月的Tak1ΔHEP小鼠的肝细胞中的水平升高。然而，Tak1/TGFBR2ΔHEP小鼠没有这种表型，它们的肝细胞没有自发细胞死亡或代偿性增殖。Tak1-Δ小鼠肝细胞经转化生长因子-β孵育后，不能激活p38、c-jun氨基末端激酶或核因子-SmadB，相反，转化生长因子-κ介导的细胞死亡和Smad2/3的磷酸化程度增加。阻断Smad通路可抑制转化生长因子-β介导的Tak1−/−肝细胞死亡。因此，阻断Smad4可以减少Tak1ΔHEP小鼠的自发肝损伤、炎症、纤维化和肝细胞癌的发生。抗凋亡蛋白Bclxl、β-catenin、结缔组织生长因子和血管内皮生长因子在Tak1/ΔΔ小鼠肝癌中表达增加，而在Tak1/TGFBR2 TGFBR2 Hep小鼠中无表达。注射N-亚硝基二乙胺可诱导野生型小鼠肝细胞癌的形成，但对Δ-HEP小鼠的诱导作用较小。转化生长因子-β通过在肿瘤形成的早期阶段诱导肝细胞凋亡和代偿性增殖，以及在肿瘤进展过程中诱导抗凋亡、致癌和血管生成因子的表达来促进Tak1ΔHEp小鼠肝癌的发展。
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. 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. 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. 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.
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影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
影响因子：
13.5
作者：
Mazzocca, Antonio;Fransvea, Emilia;Giannelli, Gianluigi
通讯作者：
Giannelli, Gianluigi
影响因子：
8
作者：
Kanzler, S;Meyer, E;Blessing, M
通讯作者：
Blessing, M
DOI：
10.1196/annals.1322.051
发表时间：
2004-01-01
期刊：
SIGNAL TRANSDUCTION AND COMMUNICATION IN CANCER CELLS
影响因子：
--
作者：
Cervello, M;Giannitrapani, L;Montalto, G
通讯作者：
Montalto, G
影响因子：
13.5
作者：
Morris, Shelli M.;Baek, Ji Yeon;Koszarek, Amanda;Kanngurn, Samornmas;Knoblaugh, Sue E.;Grady, William M.
通讯作者：
Grady, William M.