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

Cell Death Dis. 2019 Aug 14;10(8):619. doi: 10.1038/s41419-019-1828-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / genetics
  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Fatty Acid Synthase, Type I / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Hep G2 Cells
  • Hepatocytes / metabolism
  • Humans
  • Lipid Metabolism / genetics
  • Lipids / biosynthesis
  • Lipids / genetics
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mice
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / pathology
  • STAT5 Transcription Factor / genetics*
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1 / genetics*
  • TOR Serine-Threonine Kinases / genetics*

Substances

  • Lipids
  • STAT5 Transcription Factor
  • Sterol Regulatory Element Binding Protein 1
  • Acetyltransferases
  • aminoglycoside N1-acetyltransferase
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases