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Farnesoid X receptor antagonizes JNK signaling pathway in liver carcinogenesis by activating SOD3

Yan-Dong Wang1, Wei-Dong Chen, Cunbao Li

  • 1State Key Laboratory of Chemical Resource Engineering (Y.-D.W., C.G., X.L.), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China; Pathogenic Organisms and Immunology Lab (W.-D.C., C.L.), School of basic medical science, Inner Mongolia Medical University, Hohhot, 010110, Inner Mongolia, People's Republic of China; Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery (W.D.C., Y.L., H.Q., H.S., J.K.), School of Medicine, Henan University, Kaifeng, 475004, Henan, People's Republic of China; and Division of Molecular Diabetes Research (F.Y., X.W., W.H.), Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010.

Molecular Endocrinology (Baltimore, Md.)
|December 16, 2014
PubMed

Insights

Farnesoid X receptor (FXR) suppresses liver cancer by activating superoxide dismutase 3 (SOD3) to reduce reactive oxygen species and inhibit c-Jun N-terminal kinase (JNK) signaling.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Oncology

Background:

  • The farnesoid X receptor (FXR) is a critical regulator of liver metabolism and homeostasis.
  • Dysregulation of signaling pathways, including c-Jun N-terminal kinase (JNK), contributes to liver carcinogenesis.

Purpose of the Study:

  • To investigate the novel role of FXR in antagonizing JNK signaling in liver cancer.
  • To elucidate the mechanism by which FXR influences JNK activity and liver carcinogenesis.

Main Methods:

  • Utilized FXR knockout mice and JNK1 deletion models to assess JNK phosphorylation and tumor development.
  • Employed cell-based assays with human hepatoblastoma cells and primary mouse hepatocytes to evaluate FXR's effect on JNK phosphorylation and reactive oxygen species (ROS) production.
  • Conducted gene expression analysis, reporter assays, EMSA, and ChIP assays to identify SOD3 as a direct FXR target gene.

Main Results:

  • FXR deficiency led to elevated JNK phosphorylation in mouse liver, and JNK1 deletion reduced diethylnitrosamine-induced tumors in FXR(-/-) mice.
  • FXR activation alleviated JNK phosphorylation and ROS production induced by H₂O₂ or tetradecanoylphorbol acetate.
  • FXR directly activated superoxide dismutase 3 (SOD3) transcription, an antioxidant enzyme, which was crucial for inhibiting H₂O₂-induced JNK phosphorylation.

Conclusions:

  • FXR antagonizes JNK signaling in liver carcinogenesis by upregulating SOD3 expression, thereby suppressing ROS production.
  • FXR acts as a novel JNK suppressor, suggesting its potential as a therapeutic target for liver cancer treatment.

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