Transforming Growth Factor–β Signaling in Hepatocytes Promotes Hepatic Fibrosis and Carcinogenesis in Mice With Hepatocyte-Specific Deletion of TAK1

Abstract

BACKGROUND & AIMS 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.

Association between transforming growth factor-β1 -509 C>T variants and hepatocellular carcinoma susceptibility: a meta-analysis

“…In particular, the role of this cytokine during the early stages of hepatocarcinogenesis is poorly understood. However, a recent experimental study demonstrated that TGF-β signaling contributes to tumor promotion during the early stages of tumorigenesis [33]. Furthermore, an animal study suggested that hepatoma-initiating cells may be derived from hepatic progenitor cells exposed to chronic and constant TGF-β stimulation in the cirrhotic liver [34].…”

TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis

“…Since TAK1 controls activation of both IKK/NF-κB and JNK pathways, its role in liver pathophysiology has been hard to predict. We and others have previously demonstrated that ablation of Tak1 in hepatocytes results in spontaneous hepatocyte death, inflammation, fibrosis, and HCC development; these phenotypes depends on TNF and TGFβ receptor signaling (5,6) and are more dramatic than the phenotypes observed in mice with hepatocytespecific deletion of IKKβ or IKKγ/NEMO (5,(7)(8)(9).…”

The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

“…In the past fifteen years, our group and others have ascertained the roles of innate immune signaling underlying the development of cancer and cardiometabolic diseases [11,12]. Of note, our findings demonstrate that some elements of innate immune signaling pathways influence the initiation and progression of these diseases in an immune-independent manner [13].…”

“…Two critical studies have indicated that TAK1 acts as a gatekeeper that suppresses carcinogenesis in the liver by activating NF-κB [12,105]. TAK1 also participates in autophagy and fatty acid oxidation through the 5′ AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1) axis, thereby suppressing hepatosteatosis and carcinogenesis in the liver [106].…”