PUMA-mediated apoptosis drives chemical hepatocarcinogenesis in mice

Hepatology. 2011 Oct;54(4):1249-58. doi: 10.1002/hep.24516.


Hepatocyte death and proliferation contribute to hepatocellular carcinoma development after carcinogen exposure or chronic liver inflammation. However, the role and the molecular targets of hepatocyte death in relation to compensatory proliferation have not been fully characterized. In this study, we investigated the role of p53 up-regulated modulator of apoptosis (PUMA), a BH3-only protein important for both p53-dependent and -independent apoptosis, in a diethylnitrosamine (DEN)-induced liver carcinogenesis model. PUMA deficiency significantly decreased the multiplicity and size of liver tumors. DEN treatment induced p53-independent PUMA expression, PUMA-dependent hepatocyte death, and compensatory proliferation. Furthermore, inhibition or deletion of c-jun N-terminal kinase 1 (JNK1) abrogated PUMA induction, hepatocyte death, and compensatory proliferation.

Conclusion: These results provide direct evidence that JNK1/PUMA-dependent apoptosis promotes chemical hepatocarcinogenesis through compensatory proliferation, and suggest apoptotic inducers as potential therapeutic targets in liver injury and cancer.

Publication types

  • Comparative Study

MeSH terms

  • Alanine Transaminase
  • Animals
  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Biopsy, Needle
  • Blotting, Western
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology*
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Diethylnitrosamine / pharmacology
  • Disease Models, Animal
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Immunohistochemistry
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Random Allocation
  • Real-Time Polymerase Chain Reaction
  • Sensitivity and Specificity
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation


  • Apoptosis Regulatory Proteins
  • PUMA protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Diethylnitrosamine
  • Alanine Transaminase
  • Mitogen-Activated Protein Kinase 8