Dataset Information

MTOR direct crosstalk with STAT5 promotes de novo lipid synthesis and induces hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) can be the last step of nonalcoholic fatty liver disease (NAFLD) evolution, and the main characteristic of NAFLD is alteration in lipid metabolism. However, the mechanisms of abnormal lipid metabolism in NAFLD and HCC progression are yet to be identified. Here, we demonstrate that liver-specific activation of mTORC1 promoted the expression of lipid synthesis genes and lead to the development of spontaneous HCC. Genetic mouse models developed spontaneous HCC along with increased expressions of SREBP1, ACC1 and FASN. In addition, high levels of p-STAT5 were observed in the livers and particularly evident in the tumor area. And the synthesis of p-STAT5 was increased in patients along with the increase in SREBP1 synthesis in clinical samples. Moreover, mTORC1 interacts with and phosphorylates the STAT5 in hepatocytes. In conclusion, our data suggested that mTORC1 upregulates SREBP1 transcription via crosstalk with the STAT5 pathway which contributes to the NAFLD-related HCC pathogenesis. And the inhibitor of SREBP1 and mTOR may help to prevent HCC in clinical NAFLD patients.

SUBMITTER: Li T

PROVIDER: S-EPMC6692326 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

mTOR direct crosstalk with STAT5 promotes de novo lipid synthesis and induces hepatocellular carcinoma.

Li Ting T Weng Jun J Zhang Yue Y Liang Kangyan K Fu Gongbo G Li Yang Y Bai Xiaochun X Gao Yi Y Gao Yi Y

Cell death & disease 20190814 8

Hepatocellular carcinoma (HCC) can be the last step of nonalcoholic fatty liver disease (NAFLD) evolution, and the main characteristic of NAFLD is alteration in lipid metabolism. However, the mechanisms of abnormal lipid metabolism in NAFLD and HCC progression are yet to be identified. Here, we demonstrate that liver-specific activation of mTORC1 promoted the expression of lipid synthesis genes and lead to the development of spontaneous HCC. Genetic mouse models developed spontaneous HCC along w ...[more]

PMID: 31409773

Similar Datasets

Project description:Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA-treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin-2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo-Doppler work-up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = -0.412, P = 0.037 and r = -0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3-month follow-up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044-1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080-2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395-16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127-13.203; P = 0.032) were independent predictors of de novo HCC.ConclusionOur study indicates that DAA-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo-angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000-000).

Dataset Information

MTOR direct crosstalk with STAT5 promotes de novo lipid synthesis and induces hepatocellular carcinoma.

Publications

mTOR direct crosstalk with STAT5 promotes de novo lipid synthesis and induces hepatocellular carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure