The Role of JNK in the Development of Hepatocellular Carcinoma

Genes Dev. 2011 Mar 15;25(6):634-45. doi: 10.1101/gad.1989311.

Abstract

The cJun NH(2)-terminal kinase (JNK) signal transduction pathway has been implicated in the growth of carcinogen-induced hepatocellular carcinoma. However, the mechanism that accounts for JNK-regulated tumor growth is unclear. Here we demonstrate that compound deficiency of the two ubiquitously expressed JNK isoforms (JNK1 and JNK2) in hepatocytes does not prevent hepatocellular carcinoma development. Indeed, JNK deficiency in hepatocytes increased the tumor burden. In contrast, compound JNK deficiency in hepatocytes and nonparenchymal cells reduced both hepatic inflammation and tumorigenesis. These data indicate that JNK plays a dual role in the development of hepatocellular carcinoma. JNK promotes an inflammatory hepatic environment that supports tumor development, but also functions in hepatocytes to reduce tumor development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / physiopathology*
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cytokines / metabolism
  • Hepatocytes* / enzymology
  • Hepatocytes* / pathology
  • Interleukin-6 / metabolism
  • Liver / enzymology*
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / physiopathology*
  • Liver Regeneration / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 8* / deficiency
  • Mitogen-Activated Protein Kinase 8* / metabolism
  • Mitogen-Activated Protein Kinase 9 / deficiency
  • Mitogen-Activated Protein Kinase 9 / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction
  • Tumor Cells, Cultured

Substances

  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cytokines
  • Interleukin-6
  • Proto-Oncogene Proteins c-myc
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinase 8