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Transforming growth factor-? signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1.

ABSTRACT: Transforming growth factor (TGF)-?-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-? activates TAK1 and Smad signaling, which regulate cell death, proliferation, and carcinogenesis. However, it is not clear whether TGF-? signaling in hepatocytes, via TGF-? receptor-2 (Tgfbr2), promotes HCC and liver fibrosis.We generated mice with hepatocyte-specific deletion of Tak1 (Tak1?Hep), as well as Tak1/Tgfbr2DHep and Tak1/Smad4?Hep mice. Tak1flox/flox, Tgfbr2?Hep, and Smad4?Hep 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-?-mediated signaling.Levels of TGF-?, TGF-?R2, and phospho-Smad2/3 were increased in HCCs from Tak1?Hep mice, which developed liver fibrosis and inflammation by 1 month and HCC by 9 months. However, Tak1/Tgfbr2?Hep mice did not have this phenotype, and their hepatocytes did not undergo spontaneous cell death or compensatory proliferation. Hepatocytes from Tak1?Hep mice incubated with TGF-? did not activate p38, c-Jun N-terminal kinase, or nuclear factor-?B; conversely, TGF-?-mediated cell death and phosphorylation of Smad2/3 were increased, compared with control hepatocytes. Blocking the Smad pathway inhibited TGF-?-mediated death of Tak1-/- hepatocytes. Accordingly, disruption of Smad4 reduced the spontaneous liver injury, inflammation, fibrosis, and HCC that develops in Tak1?Hep mice. Levels of the anti-apoptotic protein Bcl-xL, ?-catenin, connective tissue growth factor, and vascular endothelial growth factor were increased in HCC from Tak1?Hep mice, but not in HCCs from Tak1/Tgfbr2?Hep mice. Injection of N-nitrosodiethylamine induced HCC formation in wild-type mice, but less in Tgfbr2?Hep mice.TGF-? promotes development of HCC in Tak1?Hep 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.

SUBMITTER: Yang L

PROVIDER: S-EPMC3752402 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1.

Yang Ling L Inokuchi Sayaka S Roh Yoon Seok YS Song Jingyi J Loomba Rohit R Park Eek Joong EJ Seki Ekihiro E

Gastroenterology 20130204 5

<h4>Background & aims</h4>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 live ...[more]

PMID: 23391818

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Project description:Hepatocellular carcinoma represents one of the most-rapidly spreading cancers in the world. In the majority of cases, an inflammation-driven fibrosis or cirrhosis precedes the development of the tumor. During malignant transformation, the tumor microenvironment undergoes qualitative and quantitative changes that modulate the behavior of the malignant cells. A key constituent for the hepatic microenvironment is the small leucine-rich proteoglycan decorin, known to interfere with cellular events of tumorigenesis mainly by blocking various receptor tyrosine kinases (RTK) such as EGFR, Met, IGF-IR, PDGFR and VEGFR2. In this study, we characterized cell signaling events evoked by decorin deficiency in two experimental models of hepatocarcinogenesis using thioacetamide or diethyl nitrosamine as carcinogens. Genetic ablation of decorin led to enhanced tumor occurrence as compared to wild-type animals. These findings correlated with decreased levels of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and a concurrent elevation in retinoblastoma protein phosphorylation via cyclin dependent kinase 4. Decreased steady state p21(Waf1/Cip1) levels correlated with enhanced expression of transcription factor AP4, a known transcriptional repressor of p21(Waf1/Cip1), and enhanced c-Myc protein levels. In addition, translocation of β-catenin was a typical event in diethyl nitrosamine-evoked tumors. In parallel, decreased phosphorylation of both c-Myc and β-catenin was observed in Dcn(-/-) livers likely due to the hindered GSK3β-mediated targeting of these proteins to proteasomal degradation. We discovered that in a genetic background lacking decorin, four RTKs were constitutively activated (phosphorylated), including three known targets of decorin such as PDGFRα, EGFR, IGF-IR, and a novel RTK MSPR/RON. Our findings provide powerful genetic evidence for a crucial in vivo role of decorin during hepatocarcinogenesis as lack of decorin in the liver and hepatic stroma facilitates experimental carcinogenesis by providing an environment devoid of this potent pan-RTK inhibitor. Thus, our results support future utilization of decorin as an antitumor agent in liver cancer.

Project description:Transforming growth factor beta (TGF?) plays a major role in the regulation of tumor initiation, progression, and metastasis. It is depended on the type II TGF? receptor (T?RII) for signaling. Previously, we have shown that deletion of T?RII in mammary epithelial of MMTV-PyMT mice results in shortened tumor latency and increased lung metastases. However, active TGF? signaling increased the number of circulating tumor cells and metastases in MMTV-Neu mice. In the current study, we describe a newly discovered connection between attenuated TGF? signaling and human epidermal growth factor receptor 2 (HER2) signaling in mammary tumor progression.All studies were performed on MMTV-Neu mice with and without dominant-negative T?RII (DNIIR) in mammary epithelium. Mammary tumors were analyzed by flow cytometry, immunohistochemistry, and immunofluorescence staining. The levels of secreted proteins were measured by enzyme-linked immunosorbent assay. Whole-lung mount staining was used to quantitate lung metastasis. The Cancer Genome Atlas (TCGA) datasets were used to determine the relevance of our findings to human breast cancer.Attenuated TGF? signaling led to a delay tumor onset, but increased the number of metastases in MMTVNeu/DNIIR mice. The DNIIR tumors were characterized by increased vasculogenesis, vessel leakage, and increased expression of vascular endothelial growth factor (VEGF). During DNIIR tumor progression, both the levels of CXCL1/5 and the number of CD11b+Gr1+ cells and T cells decreased. Analysis of TCGA datasets demonstrated a significant negative correlation between TGFBR2 and VEGF genes expression. Higher VEGFA expression correlated with shorter distant metastasis-free survival only in HER2+ patients with no differences in HER2-, estrogen receptor +/- or progesterone receptor +/- breast cancer patients.Our studies provide insights into a novel mechanism by which epithelial TGF? signaling modulates the tumor microenvironment, and by which it is involved in lung metastasis in HER2+ breast cancer patients. The effects of pharmacological targeting of the TGF? pathway in vivo during tumor progression remain controversial. The targeting of TGF? signaling should be a viable option, but because VEGF has a protumorigenic effect on HER2+ tumors, the targeting of this protein could be considered when it is associated with attenuated TGF? signaling.

Dataset Information

Transforming growth factor-? signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1.

Publications

Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1.

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